JP7165146B2 - Glycopeptide derivative compounds and their uses - Google Patents

Description

Cross-references to related applications

This application is filed May 22, 2017, U.S. Provisional Application No. 62/509,378; Priority is claimed from US Provisional Application No. 62/560,413, the disclosures of each of which are hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION Frequently occurring multidrug-resistant bacteria, and in particular Gram-positive bacteria, present significant challenges for the management of infections, both in the hospital setting and in the community (Krause et al. (2008)). Antimicrobial Agents and Chemotherapy 52(7), pp. 2647-2652, incorporated herein by reference in its entirety for all purposes).

Treatment of invasive Staphylococcus aureus (also known as Staphylococcus aureus) (S. aureus) infections has relied heavily on vancomycin. However, treatment and management of such infections presents therapeutic challenges, as certain S. aureus isolates, and particularly methicillin-resistant S. aureus isolates, have been shown to be resistant to vancomycin. (Shaw et al. (2005). Antimicrobial Agents and Chemotherapy 49(1), pp. 195-201; Mendes et al. (2015). Antimicrobial Agents and Chemotherapy 59(3), pp. 1811 -1814, each of which is incorporated herein by reference in its entirety for all purposes).

Because of the resistance to antibiotics exhibited by many Gram-positive organisms, and the general lack of sensitivity to existing antibiotics, there is a need for new therapeutic strategies to combat infections by these bacteria. The present invention addresses this need and other needs.
Outline of the invention

式中、
R¹は、C₁-C₁₈線状アルキル、C₁-C₁₈分枝アルキル、R⁵-Y-R⁶-(Z)_n、または

であり；
R²は-OHまたは-NH-(CH₂)_q-R⁷であり；
R³はHまたは

であり；
R⁴はHまたはCH₂-NH-CH₂-PO₃H₂であり；
nは1または2であり；
各qは無関係に1、2、3、4、または5であり；
XはO、S、NHまたはH₂であり；
各Zは、水素、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環式化合物から無関係に選ばれ；
R⁵およびR⁶は、アルキレン、アルケニレンおよびアルキニレンからなる群より無関係に選ばれ、そこで、アルキレン、アルケニレンおよびアルキニレン基は、アルコキシ、置換アルコキシ、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、カルボキシル、カルボキシルアルキル、チオアリールオキシ、チオヘテロアリールオキシ、チオヘテロシクロオキシ、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、複素環式化合物、ヘテロシクロオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、-SO-アルキル、-SO-置換アルキル、-SO-アリール、-SO-ヘテロアリール、-SO₂-アルキル、-SO₂-置換アルキル、-SO₂-アリールおよび-SO₂-ヘテロアリールからなる群より選ばれる1から3個までの置換基により随意に置換され
R⁷は-N(CH₂)₂；-N⁺(CH₂)₃；または

であり；
Yは、酸素、硫黄、-S-S-、-NR⁸-、-S(O)-、-SO₂-、-NR⁸C(O)-、-OSO₂-、-OC(O)-、-NR⁸SO₂-、-C(O)NR⁸-、-C(O)O-、-SO₂NR⁸-、-SO₂O-、-P(O)(OR⁸)O-、-P(O)(OR⁸)NR⁸-、-OP(O)(OR⁸)O-、-OP(O)(OR⁸)NR⁸-、-OC(O)O-、-NR⁸C(O)O-、-NR⁸C(O)NR⁸-、-OC(O)NR⁸-および-NR⁸SO₂NR⁸-からなる群より無関係に選ばれ；および
各R⁸は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アリール、ヘテロアリールおよび複素環式化合物からなる群より無関係に選ばれるもの
の有効な量が含まれる組成物をペイシェントに施すことを含む。 In one aspect of the invention, a method is provided for treating a bacterial infection in a patient in need thereof. In one aspect, the method of the invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

During the ceremony,
R ¹ is C ₁ -C ₁₈ linear alkyl, C ₁ -C ₁₈ branched alkyl, R ⁵ -YR ⁶ -(Z) _n , or

is;
^R2 is -OH or -NH-( _CH2 ) _q - ^R7 ;
^R3 is H or

is;
^R4 is H or _CH2 -NH _{- CH2 -} PO3H2;
n is 1 or 2;
each q is independently 1, 2, 3, 4, or 5;
X is O, S, NH or _H2 ;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
^R5 and ^R6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl
^R7 is -N( _CH2 ) ₂ ; -N ⁺ ( _CH2 ) ₃ ; or

is;
Y is oxygen, sulfur, -SS-, -NR8-, -S ⁽ O)-, _-SO2- , ^-NR8C (O)-, _-OSO2- , -OC(O)-,- ^NR8SO2- , -C(O) _NR8- , -C(O)O-, ^-SO2NR8- , _-SO2O- , -P ₍ O) ^{( OR8} )O-, -P (O)( ^OR8 ) ^NR8- , -OP(O)( ^OR8 )O-, -OP(O)( ^OR8 ) ^NR8- , -OC(O)O-, ^-NR8C (O )O-, ^{-NR8C (} O) ^NR8- , -OC ⁽ O) ^NR8- and ^-NR8SO2NR8- ; and _each R8 is hydrogen, alkyl , substituted alkyls, alkenyls, substituted alkenyls, alkynyls, substituted alkynyls, cycloalkyls, substituted cycloalkyls, cycloalkenyls, substituted cycloalkenyls, aryls, heteroaryls and heterocyclics. including applying the contained composition to the patient.

(II),
式中、
R¹は、C₁-C₁₈線状アルキル、C₁-C₁₈分枝アルキル、R⁵-Y-R⁶-(Z)_n、または

であり；
R²は-OHまたは-NH-(CH₂)_q-R⁷であり；
R³はHまたは

であり；
R⁴はHまたはCH₂-NH-CH₂-PO₃H₂であり；
nは1または2であり；
各qは無関係に1、2、3、4、または5であり；
XはO、S、NHまたはH₂であり；
各Zは、水素、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環式化合物から無関係に選ばれ；
R⁵およびR⁶は、アルキレン、アルケニレンおよびアルキニレンからなる群より無関係に選ばれ、そこで、アルキレン、アルケニレンおよびアルキニレン基は、アルコキシ、置換アルコキシ、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、カルボキシル、カルボキシルアルキル、チオアリールオキシ、チオヘテロアリールオキシ、チオヘテロシクロオキシ、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、複素環式化合物、ヘテロシクロオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、-SO-アルキル、-SO-置換アルキル、-SO-アリール、-SO-ヘテロアリール、-SO₂-アルキル、-SO₂-置換アルキル、-SO₂-アリールおよび-SO₂-ヘテロアリールからなる群より選ばれる1から3個までの置換基により随意に置換され；
R⁷は-N(CH₂)₂；-N⁺(CH₂)₃；または

であり；
Yは、酸素、硫黄、-S-S-、-NR⁸-、-S(O)-、-SO₂-、-OSO₂-、-NR⁸SO₂-、-SO₂NR⁸-、-SO₂O-、-P(O)(OR⁸)O-、-P(O)(OR⁸)NR⁸-、-OP(O)(OR⁸)O-、-OP(O)(OR⁸)NR⁸-、-NR⁸C(O)NR⁸-、および-NR⁸SO₂NR⁸-からなる群より無関係に選ばれ；および
各R⁸は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アリール、ヘテロアリールおよび複素環式化合物からなる群より無関係に選ばれるもの
の有効な量が含まれる組成物をペイシェントに施すことを含む。 In another embodiment, the method of the present invention comprises a compound of formula (II), a prodrug thereof, or a pharmaceutically acceptable salt thereof:

(II),
During the ceremony,
R ¹ is C ₁ -C ₁₈ linear alkyl, C ₁ -C ₁₈ branched alkyl, R ⁵ -YR ⁶ -(Z) _n , or

is;
^R2 is -OH or -NH-( _CH2 ) _q - ^R7 ;
^R3 is H or

is;
^R4 is H or _CH2 -NH _{- CH2 -} PO3H2;
n is 1 or 2;
each q is independently 1, 2, 3, 4, or 5;
X is O, S, NH or _H2 ;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
^R5 and ^R6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl ;
^R7 is -N( _CH2 ) ₂ ; -N ⁺ ( _CH2 ) ₃ ; or

is;
Y is oxygen, sulfur, _-SS- , ^-NR8- , -S ⁽ O)-, _-SO2- , ^-OSO2- , _-NR8SO2- , _-SO2NR8- , _-SO2 O-, -P(O)( ^OR8 )O-, -P(O)( ^OR8 ) ^NR8- , -OP(O)( ^OR8 )O-, -OP(O)( ^OR8 )NR independently selected from the group ^consisting of ^8- , ^-NR8C ₍ O) ^NR8- , and ^-NR8SO2NR8- ; and each ^R8 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, administering to the patient a composition comprising an effective amount independently selected from the group consisting of alkynyls, substituted alkynyls, cycloalkyls, substituted cycloalkyls, cycloalkenyls, substituted cycloalkenyls, aryls, heteroaryls and heterocyclics; including.

In one embodiment of the method of treating a bacterial infection, the composition comprises an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II). , wherein R ¹ is C ₆ to C ₁₆ linear alkyl. _In a further embodiment, ^R1 is C6, _C10 or _C16 alkyl. In a still further embodiment, ^R1 is _C10 alkyl. In a further embodiment, the bacterial infection is a pulmonary bacterial infection. In still further embodiments, administration comprises administration via inhalation.

In one embodiment, a method for treating a bacterial infection includes administering to a patient in need thereof a compound of Formula (I), Formula (II), or a pharmaceutical agent of Formula (I) or Formula (II). Providing acceptable salts wherein R ¹ is R ⁵ -YR ⁶ -(Z) _n is included. ^In a further embodiment, R5 is -( _CH2 ) _2- , ^R6 is -( _CH2 ) _10- , X is O; Y is ^NR8 and Z is hydrogen. , and n is 1. ^In a further embodiment, R8 is hydrogen. As such, one embodiment of the present invention includes compounds of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein ^R1 is -( _CH2 ) ₂ -NH- ( _CH2 ) ₉ - _CH3 is included. In a further embodiment, the bacterial infection is a pulmonary bacterial infection. In yet another embodiment, administering comprises administering via inhalation.

In one embodiment, a method for treating a bacterial infection includes administering to a patient in need thereof a compound of Formula (I), Formula (II), or a pharmaceutical drug of Formula (I) or Formula (II). Acceptable salts where ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 and R3 and ^{R4 are} H are included. In a further embodiment, ^R2 is OH. In yet another embodiment, administering comprises administering via an intravenous route. In a further embodiment, X is O.

In one embodiment, a method for treating a bacterial infection includes administering to a patient in need thereof a compound of Formula (I), Formula (II), or a pharmaceutical drug of Formula (I) or Formula (II). acceptable salts wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 and ^R2 is -NH-( _CH2 ) _q - ^R7 , and R ³ and R ⁴ are included to give H. In a further embodiment, administration comprises administration via an intravenous or pulmonary route. In yet another embodiment, q is 2 or 3 and ^R7 is -N( _CH2 ) ₂ . In a further embodiment, X is O.

であるものの有効量が含まれる。更なる実施形態において、R²はOHであり、ならびにR³およびR⁴はHである。さらに別の実施形態において、ハロゲンはClであり、およびqは1または2である。更なる実施形態において、施与は肺または静脈内経路を介する投与を含む。更なる実施形態では、XはOであり、およびR¹は

である。 In one embodiment of the methods provided herein, the composition applied to the patient comprises a compound of Formula (I) or Formula (II), wherein R ¹ is

An effective amount of is included. In a further embodiment, ^R2 is OH and R3 and ^{R4 are} H. In yet another embodiment, halogen is Cl and q is 1 or 2. In further embodiments, administering comprises administration via pulmonary or intravenous routes. In a further embodiment, X is O and R ¹ is

is.

であり、R²はOHであり、およびR³は

であり、およびR⁴はHであるものの有効量が含まれる。さらに別の実施形態では、ハロゲンはClであり、およびqは1または2である。更なる実施形態では、施与は静脈内経路を介した投与を含む。更なる実施形態では、XはOであり、およびR¹は

である。 In one embodiment of the methods provided herein, the composition applied to the patient comprises a compound of Formula (I) or Formula (II), wherein R ¹ is

, ^R2 is OH ^, and R3 is

and R ⁴ is H. In yet another embodiment, halogen is Cl and q is 1 or 2. In a further embodiment, administering comprises administration via an intravenous route. In a further embodiment, X is O and R ¹ is

is.

In yet another embodiment, the bacterial infection is a Gram-positive cocci infection, and the composition to be administered to a patient in need thereof comprises a compound of formula (I), formula (II), or including an effective amount of a pharmaceutically acceptable salt of Formula (I) or Formula (II) wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 . In further embodiments, the infection is a Gram-positive infection, a coccal infection, and in further embodiments, vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-resistant Enterococcus faecium (also called Enterococcus faecium, etc.) and resistant to teicoplanin (VRE Fm Van A), vancomycin-resistant Enterococcus faecium sensitive to teicoplanin (VRE Fm Van B), vancomycin-resistant Enterococcus faecalis Also called teicoplanin-resistant (VRE Fs Van A), vancomycin-resistant Enterococcus faecalis susceptible to teicoplanin (VRE Fs Van B), or penicillin-resistant Streptococcus pneumoniae, pneumococcus, Streptococcus pneumoniae, etc. ) (PRSP).

In yet another embodiment, the bacterial infection is a Gram-positive cocci infection, and the composition to be administered to a patient in need thereof comprises a compound of formula (I), formula (II), or including an effective amount of a pharmaceutically acceptable salt of formula (I) or formula (II) wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 . In a further embodiment, the infection is erythromycin-resistant (erm ^R ), vancomycin-intermediate S. aureus (VISA), heterologous vancomycin-intermediate S. aureus (hVISA), S. epidermidis (S. epidermidis) coagulase-negative staphylococci (CoNS), penicillin-intermediate S. pneumoniae (S. pneumoniae) (PISP), or penicillin-resistant S. pneumoniae (PRSP).

In yet another embodiment, R ¹ is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 , and the bacterial infection is Propionibacterium acnes. ) (skin acne), Eggerthella lenta (bacteremia) or Peptostreptococcus anaerobius (female gynecological infection). In a further embodiment, ^R2 is OH and R3 and ^{R4 are} H.

In one embodiment, the bacterial infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection and the composition administered to a patient in need thereof comprises formula (I), formula (II), or including an effective amount of a pharmaceutically acceptable salt of Formula (I) or Formula (II) wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 . In a further embodiment, the application is via a nebulizer (also called an atomizer) or a dry powder inhaler (dry powder inhaler) and the bacterial infection is a pulmonary infection. In another embodiment, the administration is intravenous and ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 ; ^R2 is OH ^, and R3 and ^R4 . is H. In a further embodiment, X is O.

The top shows the reductive amination of vancomycin leading to the glycopeptide derivative. The reaction occurs at the primary amine of vancomycin. The lower part shows the synthetic scheme of the chloroeremomycin derivative. A synthetic scheme for making the glycopeptide derivative RV40 is shown. A synthetic scheme for making the glycopeptide derivative RV79 is shown. 1 is a synthetic scheme for making alkylvancomycin derivatives. One synthetic scheme for making decylvancomycin (compound #5) is shown. 1 is a bar graph showing the minimum inhibitory concentration (MIC) (μg antibiotic/mL) for various antibiotics against 23 different S. aureus strains. FIG. 4 is a scatter plot showing the minimum inhibitory concentration (MIC) of various antibiotics (μg antibiotic/mL) against 23 different S. aureus strains. Data are plotted as geometric means with 95% confidence intervals. 1 is a bar graph showing the minimum inhibitory concentration (MIC) (μg antibiotic/mL) of various antibiotics against 12 different strains of MRSA. FIG. 2 is a scatter plot showing the minimum inhibitory concentration (MIC) (μg antibiotic/mL) of various antibiotics against 12 different MRSA strains. Data are plotted as geometric means with 95% confidence intervals. FIG. 10 is a graph showing the log reduction of CFU/mL biofilm as a function of antibiotic concentration (μg/mL). FIG. 4 is a graph showing the log reduction of CFU/mL biofilm as a function of antibiotic concentration (μg/mL). FIG. 4 is a graph showing pulmonary bacterial burden versus control in an animal model of pulmonary MRSA infection. Dose was based on body weight goals. The geometric mean was 6.4 Log _{10 CFU/g lung for control versus 3.2 Log 10 CFU} /g lung for RV40 treatment. The error is 95% Cl of the geometric mean. N=11 for controls and n=10 for RV40 treatment. P<0.0001 by Mann-Whitney U-test. FIG. 3 is a graph showing the difference in log reduction of CFU/g lung versus control treatment (nebulized inhaled saline) for various antibiotics. Dose was based on body weight goals. Data plotted as mean of log value and error are SEM. The vehicle and control for RV40 and ORI was bicine buffer, pH 9.2. The vehicle and control for vancomycin treatment was saline. N=10 for RV40, n=11 for ORI, n=9 for VAN neb, n=6 for VAN i.v. FIG. 10 is a graph showing reduction in lung CFU for inhaled RV40 targeted delivery versus control dosed at 10, 5, 2, and 1 mg/kg. Drug administration via inhalation and challenge at 12 and 24 hours after intranasal bacterial challenge infection (also referred to as bacterial challenge) with MRSA (USA300, ATCC BAA-1556) in neutropenic rats. CFUs were counted 36 hours after infection. Data plotted are means of Log CFU/g (n=10 for 10 mg/kg, n=9 for 5 and 2 mg/kg, and n=11 for the 1 mg/kg group). Error is SEM. FIG. 4 is a graph showing the difference in log reduction of CFU/g lung vs. control treatment (nebulized saline) for prophylactic dosing of RV40. Prophylactic dosing with inhaled RV40 reduces lung bacterial burden compared to controls (inhaled saline) up to 5 days before infection. Single doses of RV40 (target delivery of 10 mg/kg) were administered by inhalation. Neutropenic rats were infected with MRSA (USA300, ATCC BAA-1556) at day 0 and CFUs were counted 36 hours after challenge infection. Data are plotted as the geometric mean of CFU/g. Error bars are 95% confidence intervals (CI). Statistics are based on one-way ANOVA (p=0.001) with post-hoc Bonferroni multiple comparison test. N=11 for days -7, -5, -3, -1 treatment groups, n=10 for days +0.5 and n=8 for controls.

DETAILED DESCRIPTION OF THE INVENTION In both healthcare settings and communities (communities, communities, etc.), the high frequency of multidrug-resistant bacteria, and in particular Gram. Positive bacteria present a significant challenge for the management of infections (Krause et al. (2008). Antimicrobial Agents and Chemotherapy 52(7), pp. 2647-2652, incorporated herein by reference in its entirety for all purposes). can be used). In addition, methicillin-resistant S. aureus (MRSA) infections in cystic fibrosis (CF) patients are a concern, and clinical data on approaches to eradicate such infections are lacking (Goss and Muhlebach (2011).Journal of Cystic Fibrosis 10, pp. 298-306, incorporated herein by reference in its entirety for all purposes).

The present invention provides novel methods of treating bacterial infections, and in particular methods of treating bacterial infections, to patients in need thereof. A pharmaceutically acceptable salt addresses that need, for example, by being delivered via the pulmonary or intravenous route.

In one aspect, the invention relates to methods for treating bacterial infections, such as Gram-positive bacterial infections, and in some embodiments Gram-positive bacterial pulmonary infections. The method comprises, in one embodiment, a composition comprising an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) including being administered to patients in need of The composition can be applied by any route. In the case of pulmonary infections, in one embodiment, the composition is administered via a nebulizer, dry powder inhaler (also called dry powder inhaler) or metered dose inhaler. In another embodiment, the composition is administered intravenously.

Compounds for use in methods of treating bacterial infections, and specific methods of treatment, are discussed in detail below.

An "effective amount" of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is an amount that is capable of providing the desired therapeutic response. be. The effective amount can be referred to as a single dose as part of multiple administrations during the administration period or as the total dosage of glycopeptide given during the administration period. A treatment regimen (also referred to as a treatment dosing regimen) can include substantially the same dose for each glycopeptide administration, or can include at least one, at least two, or at least three different doses.

The term "alkyl" means a monoradical branched or unbranched saturated hydrocarbon having 1 to 40 carbon atoms, such as 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Mention the chain. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like. be. Both linear and branched alkyl groups are included by the term "alkyl."

The term "substituted alkyl" refers to an alkyl group as defined above, with from 1 to 8 substituents, such as from 1 to 5 substituents or from 1 to 3 substituents. , alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo , carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, hetero cyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2- It has one selected from the group consisting of aryl and _-SO2 -heteroaryl.

The term "alkylene" refers to a branched or unbranched saturated hydrocarbon chain diradical (also referred to as a two-terminal free radical), e.g., from 1 to 40 carbon atoms, e.g. carbon atoms, or from 1 to 6 carbon atoms. The term includes, for example, methylene ₍ CH2-), ethylene _{( -CH2CH2-} ), propylene isomers ₍ e.g., _-CH2CH2CH2- and -CH _{( CH3} ) _CCH2- ) and Others are exemplified by groups such as those of the same class.

The term "substituted alkylene" refers to an alkylene group as defined above, with from 1 to 5 substituents, such as from 1 to 3 substituents, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl , cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thio heterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- It has one selected from the group consisting of substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl. Additionally, such substituted alkylene groups include one or more (also referred to as one or more) cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic compounds fused to the alkylene group. or the fusion of two substituents on an alkylene group to form a heteroaryl group. Such fused groups can contain from 1 to 3 fused (also called fused) ring structures. Additionally, the term substituted alkylene includes alkylene groups in which from 1 to 5 alkylene carbon atoms have been replaced with oxygen, sulfur or NR-, where R is hydrogen or alkyl. Examples of substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH( _NH2 )CH2-), the ₂ -carboxypropylene isomers ( _{-CH2CH ( CO2H} )CH2- ), ethoxyethyl ( _{-CH2CH2 -} O _{- CH2CH2-} ) and the like.

The term "alkaryl" refers to the groups -alkylene-aryl and substituted alkylene-aryl, where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.

The term "alkoxy" refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-cycloalkenyl-O-, and alkynyl-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Alkyl-O-alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert (also called tertiary)-butoxy, sec (also called secondary)-butoxy, n -pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

The term "substituted alkoxy" refers to the group substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, Substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkylene and Substituted alkylene is as defined herein. Alkylalkoxy groups are also denoted as alkylene-O-alkyl and by way of example methylenemethoxy _{( -CH2OCH3} ), ethylenemethoxy _{( -CH2CH2OCH3} ), n _- propylene-iso-propoxy ( _{-CH2CH2CH2OCH} ( _CH3 ) ₂ ), methylene _- t-butoxy ( _{-CH2 -} OC( _CH3 ) ₃ ) and the like.

The term "alkenyl" has from 2 to 40 carbon atoms, such as from 2 to 10 carbon atoms or from 2 to 6 carbon atoms, and at least one, and in some embodiments, It refers to monoradicals of branched or unbranched unsaturated hydrocarbon radicals having from 1-6 sites of vinyl unsaturation. Alkenyl groups include ethenyl (-CH= _CH2 ), n-propenyl (-CH2CH= _CH2 ), isopropenyl (-C( _CH3 ) _{= CH2} ), and the like. be

The term “substituted alkenyl” refers to alkenyl groups as defined above, with 1 to 5 substituents, and examples are alkoxy, substituted alkoxy, cycloalkyl, substituted cyclo, with 1 to 3 substituents. Alkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thio heteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- selected from the group consisting of alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl have things

The term "alkenylene" has from 2 to 40 carbon atoms, such as from 2 to 10 carbon atoms or from 2 to 6 carbon atoms, and at least 1 and such as from 1-6 It refers to a diradical of a branched or unbranched unsaturated hydrocarbon group with vinyl unsaturation at the site. The term includes groups such as, for example, ethenylene (-CH ₌ CH-), propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-) and the like. exemplified by

The term "substituted alkenylene" refers to alkenylene groups as defined above, with from 1 to 5 substituents, and for example from 1 to 3 substituents, alkoxy, substituted alkoxy, cycloalkyl, substituted cyclo alkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO -substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl. Additionally, such substituted alkenylene groups may include , where the two substituents on the alkenylene group are fused.

The term "alkynyl" refers to an unsaturated hydrocarbon monoradical having 2 to 40 carbon atoms, such as 2 to 20 carbon atoms, or 2 to 6 carbon atoms. , and at least one and in some embodiments from 1 to 6 sites of acetylene (triple bond) unsaturation. Representative alkynyl groups include ethynyl (-C[identical to]CH), propargyl ( _-CH2C [identical to]CH), and the like.

The term "substituted alkynyl" refers to alkynyl groups as defined above, with 1 to 5 substituents, such as alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, with 1 to 3 substituents. , cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thio heterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- It has one selected from the group consisting of substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl.

The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon, having 2 to 40 carbon atoms, such as 2 to 10 carbon atoms or 2 to 6 carbon atoms, and At least one, and in some embodiments, has from 1-6 sites of acetylenic (triple bond) unsaturation. Representative alkynylene groups include ethynylene (-C[identical to]C-), propargylene ( _-CH2C [identical to]C-).

The term "substituted alkynylene" refers to an alkynylene group as defined above, with from 1 to 5 substituents, such as from 1 to 3 substituents, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl , cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thiohetero aryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl , -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl have

The term "acyl" refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)- , cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic -C(O)- , wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic compounds are as defined herein.

The term "acylamino" or "aminocarbonyl" refers to the group -C(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or , or wherein both R groups join to form a heterocyclic group (e.g., morpholino), where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as specified in

The term "aminoacyl" refers to the group -NRC(O)R, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or a heterocyclic compound, where alkyl, Substituted alkyl, aryl, heteroaryl and heterocyclic compounds are as defined herein.

The term "aminoacyloxy" or "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkylaryl, heteroaryl, or heterocyclic .

The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl -C(O)O-, heteroaryl-C(O)O-, and heterocyclic compounds -C(O)O-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, Heteroaryl, and heterocyclic compounds are as defined herein.

The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms and includes a single ring (eg, phenyl) or multiple condensed (fused) rings. (multiple condensed (fused) rings) (eg naphthyl or anthryl). Representative aryls include phenyl, naphthyl and the like. Unless otherwise restricted by definition for aryl substituents, such aryl groups can be 1 to 5 substituents, for example 1 to 3 substituents, acyloxy, hydroxy, thiol, acyl , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryl oxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, sulfonamido, thioalkoxy, substituted thioalkoxy, thioaryl oxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl, -SO It can be optionally substituted with those selected from the group consisting of ₂ -heteroaryl and trihalomethyl. In one embodiment, aryl substituents are alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy or combinations thereof.

The term "aryloxy" refers to the group aryl-O-, where the aryl group is as defined above, including optionally substituted aryl groups, also as defined above. .

The term "arylene" refers to diradicals derived from aryl (including substituted aryl) as defined above, and 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1, Exemplified by 2-naphthylene and the like.

The term "amino" refers to the group _-NH2 .

The term "substituted amino" refers to the group -NRR, where each R is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted Independently selected from the group consisting of alkynyl, aryl, heteroaryl and heterocyclic, provided that both R groups are not H;

"Amino acid" refers to both naturally occurring amino acids, synthetic amino acids, and derivatives thereof. α-Amino acids include an amino group, a carboxy group, a hydrogen atom, and a carbon atom to which distinctive groups called "side chains" are attached. Side chains of naturally occurring amino acids are well known in the art and include, for example, hydrogen (eg, glycine), alkyl (eg, alanine, valine, leucine, isoleucine, proline), substituted alkyl (eg, threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryls (eg, phenylalanine and tryptophan), substituted arylalkyls (eg, tyrosine), and heteroarylalkyl (eg, histidine).

The term "carboxyalkyl" or "alkoxycarbonyl" refers to the groups "-C(O)O-alkyl", "-C(O)O-substituted alkyl", "-C(O)O-cycloalkyl", "- C(O)O-substituted cycloalkyl", "-C(O)O-alkenyl", "-C(O)O-substituted alkenyl", "-C(O)O-alkynyl" and "-C(O )O-substituted alkynyl, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl are as defined herein.

The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or polycyclic structures such as adamantanyl, and Others of the same kind, etc. are included.

The term "substituted cycloalkyl" refers to a cycloalkyl group, with 1 to 5 substituents, and such as 1 to 3 substituents, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryl oxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl; have.

The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a monocyclic ring and at least one internal point of unsaturation. Examples of suitable cycloalkenyl groups include cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, to name a few.

The term "substituted cycloalkenyl" refers to cycloalkenyl groups, with 1 to 5 substituents, and for example 1 to 3 substituents, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryl oxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl; have.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and/or iodo.

"Haloalkyl" refers to alkyl as defined herein, substituted with 1-4 halo groups as defined herein, which may be the same or different. Representative haloalkyl groups include, by way of example, trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl, and the like. and so on.

The term "heteroaryl" has from 1 to 15 carbon atoms and is selected from oxygen, nitrogen and sulfur in at least one ring moiety ("moiety" is also referred to as a split moiety). It refers to aromatic groups of 1 to 4 heteroatoms.

Unless otherwise constrained by the definition for heteroaryl substituents, such heteroaryl groups may be substituted with 1 to 5 substituents, such as 1 to 3 substituents, acyloxy, hydroxy, thiol , acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl , aryloxy, azide, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy , thioheteroaryloxy, SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2- It can be optionally substituted with those selected from the group consisting of heteroaryl and trihalomethyl. Representative aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolizinyl or benzothienyl). In one embodiment, heteroaryl is pyridyl, pyrrolyl or furyl. "Heteroarylalkyl" refers to (heteroaryl)alkyl-, where heteroaryl and alkyl are as defined herein. Representative examples include 2-pyridylmethyl and the like.

The term "heteroaryloxy" refers to the group heteroaryl-O-.

The term "heteroarylene" refers to diradical groups derived from heteroaryl (including substituted heteroaryl), as defined above, and the groups 2,6-pyridylene, 2,4-pyridylene, 1, Exemplified by 2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridinylene, 2,5-indolenyl and the like.

The term "heterocycle" or "heterocycle" means a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, for example from 1 to 4 heterocycles. It refers to a monoradical saturated unsaturated group having atoms selected from nitrogen, sulfur, phosphorus, and/or oxygen in the ring.

Unless otherwise constrained by the definition of heterocyclic substituents, such heterocyclic groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, Alkoxyamino, nitro, SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -hetero It can be optionally substituted with those selected from the group consisting of aryl. Such heterocyclic groups can have a single ring or multiple condensed rings. In one embodiment, the heterocyclic compound is morpholino or piperidinyl.

Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyl. pyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, Included are tetrahydrofuranyl, and the like, as well as N-alkoxy nitrogen-containing heterocycles.

Another class of heterocyclic compounds is known as "crown compounds", which refers to _a particular class of heterocyclic compounds having one or more repeating units of the formula [(CH2-) _aA- ], where a is equal to or greater than 2 (also said to be greater than or equal to 2) and A is at each separate occurrence 0 (O?), N, S or P can be done. Examples of crown compounds include, by way of example, [-( _CH2 ) ₃ -NH-] ₃ , [-(( _CH2 ) ₂ -O) ₄ -(( _CH2 ) ₂ -NH) ₂ ] and the like. types, etc. In one embodiment, the crown compound has 4 to 10 heteroatoms and 8 to 40 carbon atoms.

The term "heterocyclooxy" refers to the group heterocyclic compound -O-.

The term "heterocyclene" refers to diradical groups formed from heterocycles as defined herein, and is exemplified by groups such as 2,6-morpholino, 2,5-morpholino and the like. be done.

The term "oxyacylamino" or "aminocarbonyloxy" refers to the group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic A compound wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic compounds are as defined herein.

The term "spiro-attached cycloalkyl group" refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.

The term "sulfonamide" refers to the group _-SO2NRR of the formula, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or a heterocyclic compound, where alkyl , substituted alkyl, aryl, heteroaryl and heterocyclic compounds are as defined herein.

The term "thiol" refers to the group -SH.

The term "thioheteroaryloxy" refers to the group heteroaryl-S-, where the heteroaryl group is as defined above including an aryl group optionally substituted as defined above. is.

With respect to any of the above groups containing one or more substituents, it is understood that such groups do not contain substitutions or substitution patterns that are sterically impractical and/or synthetically impracticable. Furthermore, the compounds of this invention include all stereochemical isomers resulting from substitution of these compounds.

"Glycopeptide (also called glycopeptide)" refers to heptapeptide antibiotics characterized by a polycyclic peptide core optionally substituted with sugar groups. Examples of glycopeptides included in this provision are "Glycopeptides Classification, Occurrence, and Discovery" by Raymond C. Rao and Louise W. Crandall. Discovery)," ("Drugs and the Pharmaceutical Sciences" Vol. 63, edited by Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.), which is incorporated by reference. It is incorporated here in its entirety. Representative glycopeptides include A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin ), Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin, Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin (Galacardin), Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM5659, MM56597, MM56597, MM56597 7653, Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin, Telavancin, UK-68597, UK-69542, UK-72051, Included are those identified as vancomycin, and others of the same class. The term "glycopeptide" as used herein is also intended to include the general class of peptides disclosed above in the absence of a glycomoiety, ie, the aglycone series of glycopeptides. For example, removal of the disaccharide moiety attached to the phenol on vancomycin by mild hydrolysis gives the vancomycin aglycone. Also within the scope of the invention are glycopeptides to which additional sugar residues, particularly aminoglycosides, have been added in the same manner as vancosamine. In embodiments described herein, one or more of the aforementioned glycopeptides are used in combination with a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or (II) can do.

"Pharmaceutically acceptable salt" includes both acid and base addition salts. Pharmaceutically acceptable addition salts refer to those salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and They include inorganic acids such as, but not limited to, hydrochloric acid (HCl), hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids, such as, but not limited to, acetic acid. , 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphor acid, camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptone acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (e.g. as lactate), lactobionic acid, Lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid (also known as mucic acid), naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2- Naphthoic acid, nicotinic acid, oleic acid, orotic acid (also known as orotic acid), oxalic acid, palmitic acid, pamoic acid (also known as pamoic acid), propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-amino such as salicylic acid, sebacic acid, stearic acid, succinic acid, acetic acid (e.g. as acetate), tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid, and the like. formed by In one embodiment, the pharmaceutically acceptable salt is HCl, TFA, lactate or acetate.

Pharmaceutically acceptable base addition salts retain the biological effectiveness and properties of the free acids and they are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, Included are salts of such things as benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, resins of polyamines and the like. Organic bases that can be used to form pharmaceutically acceptable salts include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

(I),
式中、
R¹は、C₁-C₁₈線状アルキル、C₁-C₁₈分枝アルキル、R⁵-Y-R⁶-(Z)_n、または

であり；
R²は-OHまたは-NH-(CH₂)_q-R⁷であり；
R³はHまたは

であり；
R⁴はHまたはCH₂-NH-CH₂-PO₃H₂であり；
nは1または2であり；
各qは無関係に1、2、3、4、または5であり；
XはO、S、NHまたはH₂であり；
各Zは、水素、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環式化合物から無関係に選ばれ；
R⁵およびR⁶は、アルキレン、アルケニレンおよびアルキニレンからなる群より無関係に選ばれ、そこで、アルキレン、アルケニレンおよびアルキニレン基は、アルコキシ、置換アルコキシ、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、カルボキシル、カルボキシルアルキル、チオアリールオキシ、チオヘテロアリールオキシ、チオヘテロシクロオキシ、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、複素環式化合物、ヘテロシクロオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、-SO-アルキル、-SO-置換アルキル、-SO-アリール、-SO-ヘテロアリール、-SO₂-アルキル、-SO₂-置換アルキル、-SO₂-アリールおよび-SO₂-ヘテロアリールからなる群より選ばれる1から3個までの置換基により随意に置換され
R⁷は-N(CH₂)₂；-N⁺(CH₂)₃；または

であり；
Yは、酸素、硫黄、-S-S-、-NR⁸-、-S(O)-、-SO₂-、-NR⁸C(O)-、-OSO₂-、-OC(O)-、-NR⁸SO₂-、-C(O)NR⁸-、-C(O)O-、-SO₂NR⁸-、-SO₂O-、-P(O)(OR⁸)O-、-P(O)(OR⁸)NR⁸-、-OP(O)(OR⁸)O-、-OP(O)(OR⁸)NR⁸-、-OC(O)O-、-NR⁸C(O)O-、-NR⁸C(O)NR⁸-、-OC(O)NR⁸-および-NR⁸SO₂NR⁸-からなる群より無関係に選ばれ；および
各R⁸は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アリール、ヘテロアリールおよび複素環式化合物からなる群より無関係に選ばれるもの
の有効な量が含まれる組成物をペイシェントに施すことを含む。 In one aspect of the invention, a method is provided for treating a bacterial infection in a patient in need thereof. The method comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof:

(I),
During the ceremony,
R ¹ is C ₁ -C ₁₈ linear alkyl, C ₁ -C ₁₈ branched alkyl, R ⁵ -YR ⁶ -(Z) _n , or

is;
^R2 is -OH or -NH-( _CH2 ) _q - ^R7 ;
^R3 is H or

is;
^R4 is H or _CH2 -NH _{- CH2 -} PO3H2;
n is 1 or 2;
each q is independently 1, 2, 3, 4, or 5;
X is O, S, NH or _H2 ;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
^R5 and ^R6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl
^R7 is -N( _CH2 ) ₂ ; -N ⁺ ( _CH2 ) ₃ ; or

is;
Y is oxygen, sulfur, -SS-, -NR8-, -S ⁽ O)-, _-SO2- , ^-NR8C (O)-, _-OSO2- , -OC(O)-,- ^NR8SO2- , -C(O) _NR8- , -C(O)O-, ^-SO2NR8- , _-SO2O- , -P ₍ O) ^{( OR8} )O-, -P (O)( ^OR8 ) ^NR8- , -OP(O)( ^OR8 )O-, -OP(O)( ^OR8 ) ^NR8- , -OC(O)O-, ^-NR8C (O )O-, ^{-NR8C (} O) ^NR8- , -OC ⁽ O) ^NR8- and ^-NR8SO2NR8- ; and _each R8 is hydrogen, alkyl , substituted alkyls, alkenyls, substituted alkenyls, alkynyls, substituted alkynyls, cycloalkyls, substituted cycloalkyls, cycloalkenyls, substituted cycloalkenyls, aryls, heteroaryls and heterocyclics. including applying the contained composition to the patient.

(II),
式中、
R¹は、C₁-C₁₈線状アルキル、C₁-C₁₈分枝アルキル、R⁵-Y-R⁶-(Z)_n、または

であり；
R²は-OHまたは-NH-(CH₂)_q-R⁷であり；
R³はHまたは

であり；
R⁴はHまたはCH₂-NH-CH₂-PO₃H₂であり；
nは1または2であり；
各qは無関係に1、2、3、4、または5であり；
XはO、S、NHまたはH₂であり；
各Zは、水素、アリール、シクロアルキル、シクロアルケニル、ヘテロアリールおよび複素環式化合物から無関係に選ばれ；
R⁵およびR⁶は、アルキレン、アルケニレンおよびアルキニレンからなる群より無関係に選ばれ、そこで、アルキレン、アルケニレンおよびアルキニレン基は、アルコキシ、置換アルコキシ、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アシル、アシルアミノ、アシルオキシ、アミノ、置換アミノ、アミノアシル、アミノアシルオキシ、オキシアミノアシル、アジド、シアノ、ハロゲン、ヒドロキシル、カルボキシル、カルボキシルアルキル、チオアリールオキシ、チオヘテロアリールオキシ、チオヘテロシクロオキシ、チオール、チオアルコキシ、置換チオアルコキシ、アリール、アリールオキシ、ヘテロアリール、ヘテロアリールオキシ、複素環式化合物、ヘテロシクロオキシ、ヒドロキシアミノ、アルコキシアミノ、ニトロ、-SO-アルキル、-SO-置換アルキル、-SO-アリール、-SO-ヘテロアリール、-SO₂-アルキル、-SO₂-置換アルキル、-SO₂-アリールおよび-SO₂-ヘテロアリールからなる群より選ばれる1から3個までの置換基により随意に置換され
R⁷は-N(CH₂)₂；-N⁺(CH₂)₃；または

であり；
Yは、酸素、硫黄、-S-S-、-NR⁸-、-S(O)-、-SO₂-、-OSO₂-、-NR⁸SO₂-、-SO₂NR⁸-、-SO₂O-、-P(O)(OR⁸)O-、-P(O)(OR⁸)NR⁸-、-OP(O)(OR⁸)O-、-OP(O)(OR⁸)NR⁸-、NR⁸C(O)NR⁸-、および-NR⁸SO₂NR⁸-からなる群より無関係に選ばれ；および
各R⁸は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、アリール、ヘテロアリールおよび複素環式化合物からなる群より無関係に選ばれるように規定される。 Another aspect of the invention relates to a method of treating a patient for bacterial infection. The method comprises administering to a patient in need of treatment a composition comprising an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof. Formula (II) is:

(II),
During the ceremony,
R ¹ is C ₁ -C ₁₈ linear alkyl, C ₁ -C ₁₈ branched alkyl, R ⁵ -YR ⁶ -(Z) _n , or

is;
^R2 is -OH or -NH-( _CH2 ) _q - ^R7 ;
^R3 is H or

is;
^R4 is H or _CH2 -NH _{- CH2 -} PO3H2;
n is 1 or 2;
each q is independently 1, 2, 3, 4, or 5;
X is O, S, NH or _H2 ;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
^R5 and ^R6 are independently selected from the group consisting of alkylene, alkenylene and alkynylene, wherein the alkylene, alkenylene and alkynylene groups are alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy , substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -substituted alkyl, _-SO2 -aryl and _-SO2 -heteroaryl
^R7 is -N( _CH2 ) ₂ ; -N ⁺ ( _CH2 ) ₃ ; or

is;
Y is oxygen, sulfur, _-SS- , ^-NR8- , -S ⁽ O)-, _-SO2- , ^-OSO2- , _-NR8SO2- , _-SO2NR8- , _-SO2 O-, -P(O)( ^OR8 )O-, -P(O)( ^OR8 ) ^NR8- , -OP(O)( ^OR8 )O-, -OP(O)( ^OR8 )NR ^8- , ^NR8C ₍ O) ^NR8- , and ^-NR8SO2NR8- ; and each ^R8 is ^hydrogen , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyls, cycloalkyls, substituted cycloalkyls, cycloalkenyls, substituted cycloalkenyls, aryls, heteroaryls and heterocyclics.

Compounds of formula (I) and formula (II) are, in one embodiment, synthesized by the methods provided in U.S. Pat. No. 6,455,669 and/or U.S. Pat. Incorporate them in their entirety here. Further synthetic methods are provided herein in the Examples section. Other preparative steps and methods that can be employed are disclosed in U.S. Patent No. 6,392,012; U.S. Patent Application Publication No. 2017/0152291; are incorporated herein by reference in their entirety. The method described in International Publication No. WO2018/08197, the disclosure of which is incorporated by reference in its entirety, can also be employed. Synthetic schemes are also provided herein in the Examples section.

であり、およびR²はOHであるものは、米国特許出願公開第2017/0152291号において提供される方法に従って合成され、その開示は参照によってその全体を組み込む。 In one embodiment, compounds of formula (I) and formula (II), examples are those wherein R ¹ is

and R ² is OH were synthesized according to the methods provided in US Patent Application Publication No. 2017/0152291, the disclosure of which is incorporated by reference in its entirety.

（例は、

）であり、およびXがOであるもの）は、-NH-(CH₂)_q-R⁷の溶液（例は：-NH-(CH₂)₃-N(CH₂)₂、-NH-(CH₂)₃-N⁺(CH₂)₃、または

の溶液）、N-メチルモルホリンおよびHBTUにより25℃にて処理することができる。反応混合物を25℃で5分間撹拌し、および25℃にてH₂Oにおいて50％MeOHを加えることによりクエンチすることができる。混合物をセミ分取逆相HPLCによって精製して、化合物を白色フィルムとして供給することができる。 In an embodiment, ^R2 is -NH-( _CH2 ) _q - ^R7 and the amide coupling is as described in Yarlaggadda et al. (2014). J. Med. Chem. 57, pp. 4558-4568, the disclosure of which is hereby incorporated by reference in its entirety for all purposes. . For example, solutions of vancomycin or other glycopeptide derivatives (eg, compounds of formula (I) or formula (II), where R ¹ is

(For example,

) and X is O) is a solution of -NH-( _CH2 ) _q - ^R7 (e.g. -NH-( _CH2 ) ₃ -N( _CH2 ) ₂ , -NH- ( _CH2 ) ₃ -N ⁺ ( _CH2 ) ₃ , or

solution), N-methylmorpholine and HBTU at 25°C. The reaction mixture can be stirred at 25°C for 5 minutes and quenched by adding 50% MeOH in H ₂ O at 25°C. The mixture can be purified by semi-preparative reverse-phase HPLC to furnish the compound as a white film.

In one embodiment, the method for treating a bacterial infection provides a patient in need thereof with a compound of formula (I), formula (II), or a pharmaceutically acceptable compound of formula (I) or formula (II). salts where R ¹ does not contain a physiologically cleavable functional group. Stated another way, in one embodiment, the R ¹ group is not subject to hydrolysis or enzymatic cleavage in vivo (in vivo).

In another embodiment, a method for treating a bacterial infection comprises a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or formula (II), wherein R ¹ includes no amide or ester moieties applied to patients in need thereof.

In one embodiment, a method for treating a bacterial infection comprises a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R ¹ is R5 ^{- YR6-} (Z) _n to patients in need thereof. ^In a further embodiment, R5 is -( _CH2 ) _2- , ^R6 is -( _CH2 ) _10- , X is O, Y is ^NR8 and Z is hydrogen. , and n is 1. ^In a further embodiment, R8 is hydrogen. As such, one embodiment of the methods provided herein is a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or formula (II), comprising: comprising delivering to the patient a composition comprising an effective amount of wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 . In a further embodiment, X is O, ^R2 is OH ^, and R3 and ^R4 are H. In still further embodiments, administration is via an intravenous or pulmonary route.

In one embodiment of this method, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R ¹ is —CH ₂ —NH A composition comprising an effective amount of -( _CH2 ) ₁₀ - _CH3 is applied to the patient. In a further embodiment, X is O, ^R2 is OH ^, and R3 and ^R4 are H. In still further embodiments, administration is via an intravenous or pulmonary route.

In one embodiment of the method, a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, A composition comprising an effective amount of wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₁₀ - _CH3 is applied to the patient. In a further embodiment, X is O, ^R2 is OH ^, and R3 and ^R4 are H. In still further embodiments, administration is via an intravenous or pulmonary route.

In one embodiment of this method, the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R ¹ is —(CH ₂ ) A composition comprising an effective amount of ₂ -NH-( _CH2 ) ₁₁ - _CH3 is applied to the patient. In a further embodiment, X is O, ^R2 is OH ^, and R3 and ^R4 are H. In still further embodiments, administration is via an intravenous or pulmonary route.

であり；XはOまたはH₂であり；およびR²は-NH-(CH₂)_q-R⁷である。更なる実施形態では、R²は-NH-(CH₂)₃-R⁷である。更なる実施形態では、R¹は

であり、およびR⁷は-N⁺(CH₂)₃または-N(CH₂)₂である。 In another embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is administered to a patient in need thereof, wherein R ¹ is

X is O or H2; and _R2 is -NH-( ^CH2 ) _{q -} ^R7 . In a further embodiment, ^R2 is -NH-( _CH2 ) ₃ - ^R7 . In a further embodiment, ^R1 is

and ^R7 is -N ⁺ ( _CH2 ) ₃ or -N( _CH2 ) ₂ .

In yet another embodiment, R ¹ is C ₁₀ -C ₁₆ alkyl. In a still further embodiment, ^R1 is _C10 alkyl.

またはR⁵-Y-R⁶-(Z)_nである。まだ更なる実施形態では、R¹はR⁵-Y-R⁶-(Z)_nであり、R⁵はメチレン、エチレンまたはプロピレンであり；R⁶は-(CH₂)₉-、-(CH₂)₁₀-、-(CH₂)₁₁-、または-(CH₂)₁₂-であり、ZはHであり、およびnは1である。 In yet another embodiment is a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or formula (II) ^, wherein ^R2 is OH and R3 and R ⁴ is H, and X is O but in an effective amount is sent to the patient. In a further embodiment, R ¹ is

or R5 ^{- YR6-} (Z) _n . ^In still further embodiments, ^R1 is R5 ^{- YR6- (} Z) _n , R5 is methylene, ethylene or propylene; R6 is -( _CH2 ) _9- , -( _CH2 ) _10- , -( _CH2 ) _11- , or -( _CH2 ) _12- , Z is H, and n is 1.

Yet another embodiment of the method of treating a bacterial infection provides an effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II). , where one or more hydrogen atoms are replaced by deuterium atoms.

In one embodiment, a method for treating a bacterial infection comprises a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II), wherein R ¹ involves administering R5 ^{- YR6-} (Z) _n to a patient in need thereof. ^In a further embodiment, R5 is -( _CH2 ) _2- , R6 is -( _CH2 ) _10- , Y is ^NR8 , Z is hydrogen, and n is ¹ . be. ^In a further embodiment, R8 is hydrogen.

In one embodiment of the methods provided herein, ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 .

であり、およびR⁴はHである、さらに別の実施形態において、表1の化合物が施され、式中R³はHであり、およびR⁴はCH₂-NH-CH₂-PO₃H₂である。さらに別の実施形態では、表1の化合物が施され、式中R³は

であり、およびR⁴はCH₂-NH-CH₂-PO₃H₂である。

Exemplary embodiments of compounds of Formula (I) or Formula (II) for use in methods of treating bacterial infections are provided in Table 1 below. It should be noted that the compounds can also be provided as pharmaceutically acceptable salts. The compounds in Table 1 are identified by their respective R ¹ , R ² and X groups. In one embodiment, the compounds of Table 1 are defined as having R3 and ^{R4 both} as H. In another embodiment, a compound of Table ¹ is applied, wherein R3 is

and ^R4 is H, a compound of Table ¹ is provided wherein R3 is H and ^R4 is _CH2 -NH- _CH2 - _PO3H is ₂ . In yet another embodiment, a compound of Table ¹ is applied, wherein R3 is

and ^R4 is _CH2 -NH _{- CH2 -} PO3H2.

In one embodiment, the compound is a prodrug of Formula (I) or Formula (II), eg, an alkyl ester prodrug. The alkyl group in _one embodiment is a straight chain C1- _C20 alkyl or a branched C1 _{- C20} alkyl. Attachment of the alkyl ester can be at any oxygen in the molecule as determined by the user of the method.

In one embodiment of the invention, a compound of formula (I), formula (II), or a pharmaceutically acceptable salt of formula (I) or formula (II) is sent to a patient in need thereof, wherein X is O, R ¹ is C ₁ -C ₁₈ linear alkyl, R ² is OH, and R ³ and R ⁴ are H.

_In further embodiments, R ¹ is C7 _- C17 linear alkyl _; C7 _- C10 or C6 _{- C10} linear alkyl.

In yet another embodiment, the compound of formula (I), formula (II), a prodrug thereof, or a pharmaceutically acceptable salt thereof, is sent to a patient in need thereof, wherein X is O , R ¹ is R ⁵ -YR ⁶ -(Z) _n , R ² is OH, and R ³ and R ⁴ are H.

^In a further embodiment, R5 is -( _CH2 ) _2- , R6 is -( _CH2 ) _10- , Y is ^NR8 , Z is hydrogen, and n is ¹ . be. ^In a further embodiment, R8 is hydrogen and X is O. In still further embodiments, administration is via an intravenous or pulmonary route.

In one embodiment of the invention, a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment for a bacterial infection, wherein R ¹ is -(CH ₂ ) ₂ -NH-( _CH2 ) ₉ - _CH3 , X is O, ^R2 is -NH-( _CH2 ) _q - ^{R7 ,} and R3 and ^R4 are H . In a further embodiment, q is 2 or 3 and ^R7 is -N( _CH2 ) ₂ .

であり、およびR⁴はHである。 In one embodiment of the invention, a compound of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment for a bacterial infection, wherein R ¹ is -(CH ₂ ) ₂ -NH-( _CH2 ) ₉ - _CH3 , X is O, ^R2 is OH ^, R3 is

and ^R4 is H.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a patient in need of treatment for a bacterial infection, wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 , X is O, ^R2 is OH, and R3 is H ^, and ^R4 is _CH2 -NH- _CH2 - _PO3H is ₂ .

In yet another embodiment, compounds of Formula (I) or Formula (II) are provided wherein one or more hydrogen atoms are replaced with deuterium atoms. In a further embodiment, R2- ^YR3- (Z) _n is -( _CH2 ) ² -NH-( _CH2 ) _{9 - CH3} .

In one embodiment of the methods of treatment provided herein, the compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is defined as : ^R1 is ( _CH2 ) _n1 -Y-( _CH2 ) _n2 - _CH3 , ^R2 is OH, R3 and ^{R4 are} H, n2 is an integer selected from 1 to 6 and n3 is an integer from 1 to 15. In a further embodiment, X is O. In still further embodiments, administration is via an intravenous or pulmonary route.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is sent to a patient in need of treatment for a bacterial infection, where ^R1 is ( _CH2 )-Y-( _CH2 ) _n2 - _CH3 , ^R2 is OH, R3 and ^{R4 are} H, and X is O. In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a patient in need of treatment for a bacterial infection, wherein ^R1 is ( _CH2 ) ₂ -Y-(CH ₂ ) _n2 - _CH3 , ^R2 is OH, R3 and ^{R4 are} H, and X is O; In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is sent to a patient in need of treatment for a bacterial infection, In ^R1 is ( _CH2 ) ₃ -Y-( _CH2 ) _n2 - _CH3 , _R2 is OH, R3 and ^{R4 are} H, and X is O. In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is sent to a patient in need of treatment for a bacterial infection, where ^R1 is ( _CH2 ) _1-3 -Y-( _CH2 ) ₈ - _CH3 , _R2 is OH, R3 and ^{R4 are} H, and X is O. In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is sent to a patient in need of treatment for a bacterial infection, In ^R1 is ( _CH2 ) _1-3 -Y-( _CH2 ) ₉ - _CH3 , ^R2 is OH, R3 and ^{R4 are} H, and X is O. In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

In one embodiment, a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II) is sent to a patient in need of treatment for a bacterial infection, In ^R1 is ( _CH2 ) ₂ -Y-( _CH2 ) ₁₀ - _CH3 , ^R2 is OH, R3 and ^{R4 are} H, and X is O. In a further embodiment, Y is oxygen, sulfur, -SS-, -NH-, -S(O)- or _-SO2- . In a further embodiment, Y is -NH-.

The compositions provided herein can be in the form of solutions, suspensions or dry powders. Compositions can be administered by techniques known in the art, including, but not limited to, intramuscular, intravenous, intratracheal, intranasal, intraocular, intraperitoneal, subcutaneous, and transdermal routes. Additionally, as discussed throughout, the present compositions may also be administered via the pulmonary route, eg, via inhalation using a nebulizer or dry powder inhaler.

In one embodiment, the compositions provided herein include an antibiotic of formula (I), formula (II), or a pharmaceutically acceptable compound of formula (I) or formula (II) in association with the polymer. A plurality of nanoparticles of salt are included. The plurality of nanoparticles has an average diameter of, in one embodiment, from about 50 nm to about 900 nm, such as from about 10 nm to about 800 nm, from about 100 nm to about 700 nm, from about 100 nm to about 600 nm, or from about 100 nm to about 500 nm. Up to

In one embodiment, the plurality of nanoparticles comprises a biodegradable polymer and an antibiotic of Formula (I), Formula (II), or a pharmaceutically acceptable salt of Formula (I) or Formula (II). In further embodiments, the biodegradable polymer is poly(D,L-lactide), poly(lactic acid) (PLA), poly(D,L-glycolide) (PLG), poly(lactide-co-glycolide) ( PLGA), poly(cyanoacrylate) (PCA), or combinations thereof.

In yet another embodiment, the biodegradable polymer is poly(lactic-co-glycolitic acid) (PLGA).

Nanoparticle compositions can be prepared according to methods known to those of ordinary skill in the art. For example, coacervation, solvent evaporation, emulsification, in situ polymerization, or combinations thereof can be employed (see, for example, Soppimath et al. (2001), Journal of Controlled Release 70, pp. 1 -20, incorporated herein by reference in its entirety for all purposes).

The amount of polymer in the composition can be adjusted, for example, to adjust the release profile of the compound of formula from the composition.

In one embodiment, US Pat. No. 5,874,064, US Pat. No. 5,874,064, US Pat. 5,855,913 and/or the dry powder composition disclosed in US Patent Application Publication No. 2008/0160092. The disclosures of US Pat. Nos. 5,874,064, 5,855,913 and US Patent Application Publication No. 2008/0160092 are hereby incorporated by reference in their entireties for all purposes.

In one embodiment, the compositions sent through the methods provided herein are spray dried, hollow and porous particulate compositions. For example, hollow and porous particle compositions such as those disclosed in International Publication No. WO 1999/16419, incorporated herein by reference in its entirety for all purposes, can be employed. Such particle compositions include particles having relatively thin porous walls defining large internal voids, although other void-containing or perforated structures are contemplated as well.

Compositions delivered via the methods provided herein, in one embodiment, have a bulk density of less than 0.5 g/ ^cm3 or 0.3 g/ ^cm3 , such as less than 0.1 g/ ^cm3 , or less than 0.05 g/cm3. This yields a powder with By providing particles with a very low bulk density, the minimum powder mass that can be packed into a unit dose container is reduced, which reduces the need for carrier particles. Exclude. Furthermore, while not wishing to be bound by theory, the elimination of carrier particles can minimize throat deposition and the "gag" effect, which means that large lactose particles Because of their size, they can affect the throat and upper respiratory tract.

In some embodiments, the particle compositions delivered via the methods provided herein include voids, pores, defects, hollows, spaces, interstitial spaces, interstitial spaces, interstitial spaces, etc. ), structural matrices that exhibit, define, or contain openings, perforations or holes. In one embodiment, the particle composition is provided in a "dry" state. That is, the particle composition has a water content that allows the powder to remain chemically and physically stable and readily dispersible during storage at ambient temperature. As such, the moisture content of the microparticles is typically less than 6 wt% and, for example, less than 3 wt%. In some embodiments, the water content is as low as 1% by weight. Moisture content is determined, at least in part, by the formulation and is controlled by the process conditions employed, such as inlet temperature, feed concentration, pump speed, and blowing agent type, concentration and post-drying.

A reduction in bound water can lead to an improvement in the dispersibility and flowability of phospholipid-based powders and powdered lung surfactants or particulate compositions comprising active agents dispersed in phospholipids. Possibilities for highly efficient delivery are provided.

A composition to be administered via the methods provided herein is, in one embodiment, a particulate composition comprising a compound of Formula (I) or Formula (II), a phospholipid and a polyvalent cation. In particular, the compositions of the present invention can employ multivalent cations in a phospholipid-containing, dispersible particulate composition for pulmonary administration to the respiratory tract for local or systemic therapy via aerosolization.

While not wishing to be bound by theory, the use of multivalent cations such as calcium chloride in the form of hygroscopic salts renders dry powders susceptible to moisture induced stabilization. is considered to stabilize While not wishing to be bound by theory, it is believed that such cations intercalate phospholipid membranes, thereby directly interacting with the negatively charged portion of the zwitterionic headgroup. This interaction results in increased dehydration of the head group area and condensation of acyl chain packing, all of which lead to increased thermodynamic stability of the phospholipid. Other benefits of such dry powder compositions are provided in US Pat. No. 7,442,388, the disclosure of which is incorporated herein in its entirety for all purposes.

In one embodiment, multivalent cations for use in the present invention are divalent cations. In further embodiments, the divalent cation is calcium, magnesium, zinc or iron. In one embodiment, the polyvalent cation is present to increase the Tm of the phospholipid such that the particle composition exhibits a Tm that is at least 20°C higher than its storage temperature Ts. In one embodiment, the molar ratio of polyvalent cation to phospholipid is 0.05, such as from about 0.05 to about 2.0, or from about 0.25 to about 1.0. In one embodiment, the molar ratio of polyvalent cations to phospholipids is about 0.50. In one embodiment, the polyvalent cation is calcium and is provided as calcium chloride.

According to one embodiment, the phospholipid is a saturated phospholipid. In a further embodiment, the saturated phospholipid is saturated phosphatidylcholine. The acyl chain lengths that can be employed range from about _C16 to _C22 . For example, one embodiment employs acyl chain lengths of 16:0 or 18:0 (ie, palmitoyl and stearoyl). In one phospholipid embodiment, natural or synthetic lung surfactant is provided as the phospholipid component. In this embodiment, phospholipids can constitute up to 90-99.9% w/w of lung surfactant. Suitable phospholipids according to this aspect of the invention include natural or synthetic pulmonary surfactants such as the trademarks ExoSurf, InfaSurf® ⁽ Ony, Inc.). )), Survanta, CuroSurf, and others commercially available under ALEC.

In one embodiment, the Tm of the phospholipid-glycopeptide particles is manipulated by varying the amount of multivalent cations in the composition.

Phospholipids from both natural and synthetic sources are compatible with the compositions applied by the methods provided herein and can be used in varying concentrations to form the structural matrix. Most compatible phospholipids include those that have a gel-to-liquid crystal phase transition above about 40°C. The incorporated phospholipids are, in one embodiment, relatively long chain ₍ ie, C16- _C22 ) saturated lipids, and in further embodiments saturated phospholipids are included. In still further embodiments, the saturated phospholipid is saturated phosphatidylcholine. In still further embodiments, the saturated phosphatidylcholine has an acyl chain length of 16:0 or 18:0 (palmitoyl or stearoyl). Exemplary phospholipids useful in the disclosed stabilized preparations include phosphoglycerides such as dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine, diphosphatidylglycerol. , short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, long-chain saturated phosphatidylinositols, and the like.

In addition to the phospholipid, a co-surfactant or combination of surfactants may be added via the methods provided herein, including use of one or more in the liquid phase and one or more in conjunction with the particle composition. It can be used in sending compositions. "Associated with or comprising" means that the particle composition can be incorporated, adsorbed, absorbed, coated, or formed by a surfactant. Surfactants include fluorinated and non-fluorinated compounds and include saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof. can be done. In one embodiment, including stabilized dispersions, the non-fluorinated surfactant is relatively insoluble in the suspending medium.

Compatible nonionic detergents suitable as cosurfactants in the compositions provided herein include sorbitan esters, sorbitan trioleate (Span ^{TM (} Span) 85), sorbitan sesquioleate, sorbitan Monooleate, Sorbitan Monolaurate, Polyoxyethylene (20) (Brij ^(R) S20), Sorbitan Monolaurate, and Polyoxyethylene (20) Sorbitan Monooleate, Oleyl Polyoxyethylene (2) Ether, Stearyl Included are polyoxyethylene (2) ethers, lauryl polyoxyethylene (4) ethers, glycerol esters, and sucrose esters. Block copolymers include diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including Poloxamer 188 (Pluronic® ^F -68), Poloxamer 407 ( ^Pluronic® F-127), and Poloxamer 338 included. Ionic surfactants such as sodium sulfosuccinate and fatty acid soaps may also be utilized.

Phospholipid-glycopeptide particle compositions may include additional lipids such as glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin, etc.; polymeric chain-bearing lipids such as polyethylene glycol, chitin; , hyaluronic acid, or polyvinylpyrrolidone; lipids with sulfonated monosaccharides, disaccharides, polysaccharides; fatty acids, such as palmitic acid, stearic acid, and/or oleic acid; esters, and cholesterol hemisuccinate.

In addition to the phospholipids and polyvalent cations, the particle compositions delivered via the methods provided herein also contain biocompatible, and in some embodiments biodegradable, polymers, copolymers, or blends thereof. Or other combinations may also be included. Polymers in one embodiment include polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinylpyrrolidone, polysaccharides (eg, dextran, starch, chitin, chitosan). ), hyaluronic acid, proteins (eg, albumin, collagen, gelatin, etc.).

Besides the polymeric substances and surfactants mentioned above, other excipients may be used, for example, to improve particle stiffness, production yield, emitted dose and deposition, shelf life and/or patient compliance. It can be added to the particle composition. Such optional excipients include, but are not limited to: colorants, taste-masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers. Other excipients can include, but are not limited to, sugars (also called carbohydrates), including monosaccharides, disaccharides and polysaccharides. For example, monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like; disaccharides such as lactose, maltose, sucrose. , trehalose, and the like; trisaccharides such as raffinose and the like; and other carbohydrates such as starch (hydroxyethyl starch), cyclo Such as dextrin and maltodextrin. Mixtures of carbohydrates and amino acids are also considered to be within the scope of the invention. Both inorganic (e.g. sodium chloride), organic acids and their salts (e.g. carboxylic acids and their salts such as sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc. ) and the inclusion of buffering agents can also be undertaken. Salts and/or organic solids such as ammonium carbonate, ammonium acetate, ammonium chloride or camphor (camphor) can also be employed.

According to one embodiment, the particle composition may be used in the form of a dry powder or in the form of a stabilized dispersion comprising a non-aqueous phase. The dispersions or powders of the invention may be used in combination with metered dose inhalers (MDIs), dry powder inhalers (DPIs), atomizers, or nebulizers to provide pulmonary delivery.

Although several procedures are generally compatible with making certain dry powder compositions described herein, spray drying is a particularly useful method. As is well known, spray drying is a one-step process that converts a liquid feed into dry particulate form. With respect to pharmaceutical applications, it will be appreciated that spray drying has been used to provide powdered substances for various routes of administration, including inhalation. See, e.g., M. Sacchetti and M. M. Van Oort, Inhalation Aerosols: Physical and Biological Basis for Therapy, A. J. Hickey, ed., Marcel Dekkar, New York, 1996, which is hereby incorporated by reference in its entirety for all purposes. Most often, spray drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to cause evaporation and drying of the droplets. The formulation or feed (or feedstock) to be spray dried can be any solution, suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray drying equipment. . In one embodiment, feedstocks include colloidal systems such as emulsions, reverse emulsions, microemulsions, multiple emulsions, particle dispersions, or slurries. Typically, the feed (also called feed) is atomized into a stream of warm filtered air that evaporates the solvent and carries the dry product to a collector. The air used is then discharged together with the solvent.

It will be further appreciated that spray dryers, and in particular their atomizers (also called atomizers), can be modified or customized for special applications, e.g., simultaneous spraying of two solutions using double nozzle technology. deaf. More specifically, a water-in-oil emulsion can be atomized from one nozzle, and a solution containing an anti-adherent, such as mannitol, is sprayed from a second nozzle. can be co-atomized from In one embodiment, it may be desirable to push the feed solution through a custom designed nozzle using a high pressure liquid chromatography (HPLC) pump. Examples of spray drying methods and systems suitable for making the dry powders of the present invention are disclosed in U.S. Pat. Nos. 6,077,543; 6,051,256; 6,001,336; each of which is incorporated by reference in its entirety for all purposes.

The resulting spray-dried powdered particles are typically mostly spherical in shape, nearly uniform in size, and often hollow, although the incorporated glycopeptide of formula (I) or formula (II) and There may be some irregularities in shape depending on the spray drying conditions. In one embodiment, an expanding agent (or blowing agent) is used in spray-dried powder production, as disclosed in WO99/16419, which is incorporated herein by reference in its entirety for all purposes. be Additionally, the emulsion can be included with a swelling agent as a dispersed or continuous phase. The swelling agent can be dispersed with the surfactant solution using, for example, a commercially available microfluidizer (also referred to as a microfluidizer) at a pressure of about 5000-15000 PSI. The process forms an emulsion, and in some embodiments, an emulsion stabilized by an incorporated surfactant, and comprises submicron droplets of a water-immiscible blowing agent dispersed in an aqueous continuous phase. can be done. In one embodiment, the blowing agent is a fluorinated compound (e.g., perfluorohexane, perfluorooctyl bromide, perfluorooctylethane, perfluorodecalin, perfluorobutylethane), which evaporates during the spray drying process, leaving a generally hollow, porous structure. Quality aerodynamically light microspheres are left behind. Other suitable liquid blowing agents include non-fluorinated oils, chloroform, Freons, ethyl acetate, alcohols and sugars. Nitrogen and carbon dioxide gases are also contemplated as suitable blowing agents. In one embodiment, perfluorooctylethane is the blowing agent.

Whatever the ingredient chosen, the first step in particulate production in one embodiment involves the preparation of the feedstock. A selected glycopeptide is dissolved in a solvent such as water, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, ethanol, methanol, or combinations thereof to produce a concentrated solution. Multivalent cations may be added to the glycopeptide solution or, as discussed below, to the phospholipid emulsion. Glycopeptides can also be dispersed directly in emulsions, especially for water-insoluble drugs. Alternatively, glycopeptides are incorporated in the form of solid particulate dispersions. The concentration of glycopeptide used will depend on the amount of glycopeptide desired in the final powder and the capabilities of the delivery device employed (eg, fine particle doses for MDI or DPI). If desired, a cosurfactant such as Poloxamer 188 or Span 80 can be dispersed in the annex solution. In addition, excipients such as sugars, starches, and the like can also be added.

In one embodiment, an oil-in-water emulsion containing polyvalent cations is then formed in a separate vessel. The oil employed in one embodiment is a fluorocarbon (eg perfluorooctyl bromide, perfluorooctylethane, perfluorodecalin), which is emulsified with a phospholipid. For example, polyvalent cations and phospholipids are mixed with hot distilled water (e.g., may be homogenized at 60°C). In one embodiment, 5 to 25 grams of fluorocarbon is added dropwise to the dispersed surfactant solution while mixing. The resulting polyvalent cation-containing perfluorocarbon is then treated with a high pressure homogenizer to reduce the particle size (particle size, also known as particle size) in the water emulsion. In one embodiment, the emulsion is processed at 12,000-18,000 PSI, 5 separate passes, and held at 50-80°C.

The glycopeptide solution (or suspension) and perfluorocarbon emulsion are then combined and fed into a spray dryer. In one embodiment, the two formulations are miscible. Although the glycopeptides are solubilized separately for purposes of the present discussion, it will be appreciated that in other embodiments the glycopeptides can be solubilized (or dispersed) directly in the emulsion. In such cases, the glycopeptide emulsion is simply spray dried without combining separate glycopeptide preparations.

Operating conditions, such as inlet and outlet temperature, feed rate, atomization pressure, drying air flow rate, nozzle configuration, etc., are used to produce the desired particle size and resulting dry particle production yield. can be adjusted according to the manufacturer's guidelines. Selection of appropriate equipment and processing conditions is well within the purview of skilled craftsmen. In one embodiment, the particle composition includes hollow, porous spray-dried microparticles or nanoparticles.

Particle compositions useful in the present invention may be formed by freeze drying in addition to spray drying. Those skilled in the art (also referred to as those skilled in the art) will recognize that lyophilization is a freeze-drying process in which the composition is frozen and then water sublimes therefrom. Methods for providing lyophilized particles are known to those skilled in the art. A freeze-dried cake containing fine foam-like structures can be pulverized using techniques known in the art.

In addition to the techniques described above, the glycopeptide particle compositions or glycopeptide particles provided herein can be prepared by adding a feed solution (either emulsion or aqueous) containing wall forming agents to heated oil (e.g., It can be formed using a method of rapid addition under reduced pressure to a reservoir of perflubron (or other high boiling FCs). The water and volatile solvents of the feed solution boil and evaporate rapidly. In one embodiment, the wall forming agent is insoluble in the heating oil. The resulting particles are then separated from the heated oil using filtration techniques and then dried under vacuum.

In another embodiment, the particulate composition of the present invention can also be formed using a double emulsion method. In the double emulsion method, the drug is first dispersed in a polymer dissolved in an organic solvent (eg, methylene chloride, ethyl acetate) by sonication or homogenization. This primary emulsion is then stabilized by forming multiple emulsions in a continuous aqueous phase containing emulsifiers such as polyvinyl alcohol and the like. The organic solvent is then removed by evaporation or extraction using conventional techniques and equipment. The resulting particles are washed, filtered and dried before combining them with a suitable suspending medium.

To maximize dispersibility, dispersion stability, and optimize distribution during application, the average geometric particle size of the particle composition in one embodiment is from about 0.5-50 μm, e.g., about 0.5 μm to about 10 μm, or about 0.5 to about 5 μm. In one embodiment, the average geometric particle size (or diameter) of the particle composition is less than 20 μm or less than 10 μm. In further embodiments, the average geometric diameter is ≦about 7 μm or ≦5 μm. In still further embodiments, the mass geometric diameter is ≦about 2.5 μm. In one embodiment, the particle composition includes dry, hollow particles having a diameter of from about 0.1 to about 10 μm, such as from about 0.5 to about 5 μm, and a shell thickness of about 0.1 μm to about 0.5 μm. of porous spherical shells.

In addition to the glycopeptide of Formula (I), Formula (II) or a pharmaceutically acceptable salt thereof, either in the same composition or in a different composition, one or more additional anti-infective agents are added thereto. may be included in compositions applied to patients requiring Additional anti-infective agents include additional glycopeptides, such as one of the glycopeptides described herein. Other additional anti-infectives include, but are not limited to, aminoglycosides (eg, dibekacin, K-4619, sisomycin, amikacin, dactimicin, isepamycin, rhodestreptomycin, apramycin, etimicin (also etimicin)). KA-5685, sorbistin, arbekacin, furamycetin, kanamycin, spectinomycin, astromycin, gentamicin, neomycin (also known as fradiomycin), sporalysin, bekanamycin, H107, netilmicin, streptomycin, boformycin, hygromycin , paromomycin, tobramycin, brulamycin, hygromycin B, plazomycin, verdamycin, capreomycin, inosamycin, ribostamycin, vertilmycin), tetracyclines (e.g., chlortetracycline, oxytetracycline, metacycline, doxycycline, minocycline) , sulfonamides (e.g. sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfacetamide), para-aminobenzoic acid, diaminopyrimidines (e.g. trimethoprim), quinolones (e.g. nalidixic acid, cinoxacin, profloxacin and norfloxacin), penicillins (e.g. penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, carbenicillin, carbenicillin indanyl, ticarcillin, azlocillin, mezlocillin, piperacillin), penicillinase-resistant penicillins (e.g. methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin), first-generation cephalosporins (e.g., cefadroxil, cephalexin, cefradine, cephalothin, cefapirin, cefazolin), second-generation cephalosporins (e.g., cefaclor, cefamandole, cefonicid, cefoxitin, cefotetan, cefuroxime, cefuroxime axetil; cefmetazole, cefprozil, loracarbef, ceforanide), third-generation cephalosporins (e.g., cefepime, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefixime, cefpodoxime, ceftibutene), etc. the β-lactam of (eg, imipenem, meropenem, aztreonam, clavulanic acid, sulbactam, tazobactam, and the like), beta-lactamase inhibitors (eg, clavulanic acid), chlorampheriicol, chloramphenicol call)? ), macrolides (e.g. erythromycin, azithromycin, clarithromycin), lincomycin, clindamycin, spectinomycin, polymyxin B, polymyxins (e.g. polymyxins A, B, C, D, E1 (colistin A), or E2, colistin B or C) colistin, vancomycin, telavancin, bacitracin, isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine, capreomycin, sulfones (e.g. dapsone, sulfoxone sodium, and others of the same class), clofazimine, thalidomide.

In one embodiment, a compound of Formula (I) or (II), or a pharmaceutically acceptable salt of Formula (I) or (II) is administered in combination with an aminoglycoside. In a further embodiment, the compound is of formula (I) or formula (I) wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 . In a further embodiment, the aminoglycoside is dibekacin, K-4619, sisomycin, amikacin, dactimicin, isepamycin, rodestreptomycin, apramycin, etimicin, KA-5685, sorbistin, arbekacin, framycetin, kanamycin, spectinomycin, astromycin, gentamicin, neomycin, sporalysin, bekanamycin, H107, netilmicin, streptomycin, boformycin, hygromycin, paromomycin, tobramycin, brulamycin, hygromycin B, plazomycin, verdamycin, capreomycin, inosamycin, ribostamycin or vertilmicin. In a further embodiment, the aminoglycoside is amikacin or gentamicin. In a further embodiment the aminoglycoside is gentamicin.

Methods are provided for treating bacterial infections, such as those caused by Gram-positive microorganisms. While not wishing to be bound by any particular theory, it is believed that the ^R1 group conjugated to the glycopeptides provided herein promotes cellular uptake of the glycopeptides at the site of infection, eg, macrophage uptake.

In one embodiment, the infection is a Gram positive cocci infection, such as Staphylococcus, Enterococcus or Streptococcus say) infection. In one embodiment, Streptococcus pneumoniae (also known as Streptococcus pneumoniae?) is diagnosed as community-acquired pneumonia or pyogenic meningitis. be treated in the patient who received it. An enterococcal infection is treated in one embodiment in a patient diagnosed with a urinary-catheter related infection. Staphylococcal infections, e.g., S. aureus, are treated in one embodiment in patients diagnosed with mechanical ventilation-associated pneumonia .

Over the past decades, the susceptibility of Gram-positive cocci to antibacterials for the treatment of infections has decreased. For examples, see Alvarez-Lerma et al. (2006) Drugs 66, pp. 751-768, which is hereby incorporated by reference in its entirety for all purposes. As such, in one aspect, the present invention addresses this need, comprising a composition comprising an effective amount of a compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof. is provided in a method of treating a patient in need thereof for Gram-positive coccal infections that are resistant to different antimicrobial agents. For example, in one embodiment, the Gram-positive coccal infection is a penicillin-resistant or vancomycin-resistant bacterial infection. In a further embodiment, the resistant bacterial infection is a methicillin-resistant Staphylococcus infection, such as a methicillin-resistant S. aereus or a methicillin-resistant Staphylococcus epidermidis infection. In another embodiment, the resistant bacterial infection is an oxacillin-resistant staphylococcal (e.g., S. aureus) infection, a vancomycin-resistant enterococcal infection or a penicillin-resistant streptococcal (e.g., S. pneumoniae) infection. Infection. In yet another embodiment, the Gram-positive cocci infection is vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis ( MRSE), vancomycin-resistant Enterococcus faecium (also called Faecium) that is also resistant to teicoplanin (VRE Fm Van A), vancomycin-resistant Enterococcus faecium that is sensitive to teicoplanin (VRE Fm Van B), Vancomycin-resistant Enterococcus faecalis that is also resistant to teicoplanin (VRE Fs Van A), vancomycin-resistant Enterococcus faecalis that is sensitive to teicoplanin (VRE Fs Van B), or penicillin-resistant Streptococcus pneumoniae (VRE Fs Van B) PSRP).

According to one embodiment, Gram-positive bacteria, including but not limited to genera Staphylococcus, Streptococcus, Enlerococcus, Bacillus, Corynebaclerium, Nocardia Methods are provided for treating infections by including (Nocardia), Clostridium, and Listeria. In one embodiment, the infection is by Gram-positive cocci. In a further embodiment the infection is a pulmonary infection. In another embodiment, the infection is Clostridium difficile (also known as Clostridium difficile) infection.

In yet another embodiment, the bacterial infection is Propionibacterium acnes (skin acne), Eggerthella lenta (bacteria) or Peptostreptococcus anaerobius (gynecological infection). In a further embodiment, the composition to be applied to a patient in need thereof is a compound of formula (I) or formula (II), wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 and X is O.

Staphylococcus is a Gram-positive, non-motile bacterium that colonizes the skin and mucous membranes. Staphylococci occur in spherical and grape-like microscopic clusters. The natural habitat of Staphylococcus is the nose; it can be isolated in 50% of normal individuals. 20% of people are cutaneous carriers and 10% carry Staphylococcus in their gut. Examples of Staphylococcal infections treatable by the methods and compositions provided herein include S. aureus, S. epidermidis, S. auricularis, S. carnosus, S. haemolyticus. (also known as S. haemolyticus, Staphylococcus), S. hyicus, S. intermedius, S. lugdunensis, S. saprophytics (S. saprophyticus, Staphylococcus saprophyticus?), S. sciuri, S. simulans, and S. warneri.

About 20 species of Staphylococcus have been reported, but only Staphylococcus aureus and Staphylococcus epidermis (Staphylococcus epidermidis?) are their interaction with humans. known to be important in function.

In one embodiment, the Staphylococcus species is resistant to penicillins, such as methicillin. In a further embodiment, the Staphylococcus species is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). The Staphylococcus infection is, in another embodiment, a methicillin-susceptible S. aereus (MSSA) infection, a vancomycin-intermediate S. aereus (VISA) infection, or a vancomycin-resistant S. aereus (VRSA) infection.

Although S. aureus primarily colonizes the nasal cavity, it can be found regularly in most anatomical locations, including the cutaneous oral cavity and the gastrointestinal tract. In one embodiment, a S. aureus infection is treated using a method and/or composition provided herein. In a further embodiment, the S. aureus infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection. In another embodiment, the S. aureus infection is a S. aereus (VISA) infection, or a vancomycin-resistant S. aereus (VRSA) infection.

S. aureus infection may be acquired in a relevant health care (also referred to as healthcare, medical, etc.), i.e., hospital or other healthcare setting, or community-acquired. be able to.

In one embodiment, a Staphylococcal infection treated by a method and/or composition provided herein causes endocarditis or sepsis. As such, a patient in need of treatment with a method and/or composition provided herein is, in one embodiment, an endocarditis patient. In another embodiment, the patient is a sepsis patient.

である化合物である。 In one embodiment, the bacterial infection is erythromycin-resistant (erm ^R ), vancomycin-intermediate S. aureus (VISA), heterologous vancomycin-intermediate S. aureus (hVISA), S. epidermidis coagulase-negative Staphylococci ( CoNS), penicillin-intermediate S. pneumoniae (PISP), or penicillin-resistant S. pneumoniae (PRSP). In still further embodiments, administering comprises administering via inhalation. In still further embodiments, compounds of Formula (I) or Formula (II) are those wherein ^R1 is -( _CH2 ) ₂ -NH-( _CH2 ) ₉ - _CH3 or

is a compound.

Streptococci are Gram-positive, non-motile cocci that divide in one plane to produce chains of cells. Primary pathogens include S. pyrogenes (S. pyogenes?) and S. pneumoniae, although other species can be opportunistic. S. pyrogenes is a major cause of bacterial pharyngitis and tonsillitis. It can also lead to sinusitis (also called sinusitis), otitis, arthritis, and bone infections. Some strains are skin-preferring and produce either superficial (also called impetigo, pimple, etc.) or deep (cellulitis) infections.

S. pneumoniae is the leading cause of bacterial pneumonia in adults, and in one embodiment, infection by S. pneumoniae is treated via a method and/or composition provided herein. Its toxicity is dictated by its capsule (also called capsule). Toxins produced by Streptococcus include: streptolysin (S&O), NADase (also called NAD nucleosidase), hyaluronidase, streptokinase, DNAses (also called deoxyribonuclease, DNase, etc.), erythrotoxin (which damages blood vessels). causes scarlet fever rash; bacterial cells must be lysogenized by a toxin-encoding phage). Examples of Streptococcus infections treatable by the compositions and methods provided herein include S. agalactiae, S. anginosus, S. bovis, S. canis ( S. canis), S. constellatus (S. constellatus), S. dysgalactiae (S. dysgalactiae), S. equi (S. equi), S. equinus (S. equinus), S. Mae (S. Mae), S. intermedins (S. intermedius, S. intermedius?), S. mitis (S. mitis), S. mutans (S. mutans), S. oralis (S. Oralis), S. parasanguinis, S. peroris, S. pneumoniae, S. pyogenes, S. ratti (S. salivarius), S. salivarius ssp. (Streptococcus salivarius spp. thermophilus?), S. sanguinis ), S. sobrinus (S. sobrinus), S. suis (S. suis), S. uteris (S. uteris), S. vestibularis (S. vestibularis), S. viridans (S. viridans), and S. Includes S. zooepidemicus (S. zooepidemicus).

The genus Enterococci consists of Gram-positive, facultative anaerobes that are oval in shape and appear as short, paired, or single cells on smears. Enterococci are human pathogens that are increasingly resistant to antimicrobial agents. Examples of Enterococci treatable by the methods and compositions provided herein include E. avium, E. durans, E. faecalis, E. faecium. faecium), E. gallinarum, and E. solitarius.

In one embodiment of the methods provided herein, a patient in need thereof is treated for Enterococcus faecalis (E. faecalis) infection. In a further embodiment the infection is a pulmonary infection. In another embodiment, a patient in need thereof is treated for Enterococcus faecium (E. faecium) infection. In a further embodiment the infection is a pulmonary infection. In one embodiment, a patient in need thereof is treated for an Enterococcal infection resistant or susceptible to vancomycin or resistant or susceptible to penicillin. In a further embodiment, the infection is an E. faecalis or E. faecium infection.

Bacteria of the genus Bacillus are aerobic, endospore-forming, Gram-positive bacilli, and infections by such bacteria are treatable via the methods and compositions provided herein. Bacillus species are found in soil, air, and water and are involved in various chemical transformations. In one embodiment, methods are provided herein for treating a Bacillus anthracis (B. anthracis) infection with a glycopeptide composition. Bacillus anthracis, an infection of which causes Anthrax, is brought about by direct contact with infected herbivores or indirect contact through their products. Clinical forms include cutaneous anthrax, from handling infected material, intestinal anthrax, from eating infected meat, and inhalation anthrax, from inhalation of spore-bearing dust. The route of administration of the glycopeptide will vary depending on how the patient acquires the B. anthracis infection. For example, in the case of inhalational anthrax, the patient is treated via a dry powder inhaler (DPI), nebulizer or metered dose inhaler (MDI) in one embodiment.

Several other Bacillus species, notably B. cereus, B. subtilis and B. licheniformis, are known to cause bacteremia/septicemia, Endocarditis, meningitis, and infections of the wounds, ears, eyes, respiratory tract, urinary tract, and gastrointestinal tract are periodically associated with and therefore treatable by the methods and compositions provided herein. . Examples of pathogenic Bacillus species whose infections can be treated by the methods and compositions provided herein include, but are not limited to, B. anthracis (B. anthracis), B. cereus and B. coagulans (B. coagulans) are included.

Corynebacteria are small, generally non-motile, Gram-positive, non-sporulating, pleomorphic bacilli, and infections by these bacteria are treatable via the methods provided herein. be. Corybacterium diphtheria (Corynebacterium diphtheriae?) is the etiological agent of diphtheria, a disease of the upper respiratory tract that primarily affects children, and herein It is treatable via the methods provided. Examples of other Corynebacterium species treatable by the methods and compositions provided herein include Corynebacterium diphtheria, Corynebacterium diphtheriae?, Corynebacterium pseudotuberculosis. Bacteria pseudotuberculosis, also known as ovine pseudotuberculosis), Corynebacterium tenuis, Corynebacterium striatum, and Corynebacterium minutissimum.

Bacteria of the genus Nocardia are Gram-positive partially acid-fast rods, which grow slowly in branching chains resembling fungal hyphae that resemble mycelium. . Three species cause nearly all human infections: N. asteroides, N. brasiliensis and N. caviae, and have such infections Patients can be treated with the compositions and methods provided herein. Infection is due to inhalation of airborne bacilli from environmental agents (soil or organic matter). Other Nocardia species treatable by the methods provided herein include N. aerocolonigenes, N. africana, N. argentinensis, N. asteroides. , N. blackwellu, N. brasiliensis, N. brevicalena, N. cornea (N. cornea, Nocardia carnea?), N. caviae, N. cerradoensis, N. corallina, N. cyriacigeorgica, N. dassonvillei, N. elegans, N. farcinica N. farcinica), N. nigiitansis, N. nova, N. opaca, N. otitidis-cavarium, Nocardia otitidiscaviarum Cardia otaitidiscabiaramuo?), N. paucivorans, N. pseudobrasiliensis, N. rubra, N. transvelencesis belensis), N. uniformis, N. vaccinii, and N. veterana.

Clostridia are spore-forming, Gram-positive anaerobes, and infections by such bacteria are treatable via the methods and compositions provided herein. In one embodiment, one of the methods provided herein is used to treat Clostridium tetani (C. tetani) infection, the causative agent of tetanus. In another embodiment, one of the methods provided herein is for treating Clostridium botidinum (C. botidinum) infection, the causative agent of botulism. used for In yet another embodiment, one of the methods provided herein is used to treat C. perfringens infection, one of the causative agents of gas gangrene. Other Clostridium species treatable by the methods of the invention include C. difficile, C. perfringens, and/or C. sordellii. In one embodiment, the infection treated is a C. difficile infection.

Listeria are non-spore-forming, non-branching, Gram-positive bacilli that occur individually or form short chains. Listeria monocytogenes (L. monocytogenes) is the causative agent of listeriosis, and in one embodiment, a patient infected with L. monocytogenes is treated by one of the methods and compositions provided herein. be treated. Examples of Listeria species treatable by the methods and compositions provided herein include L. grayi, L. innocua, L. ivanovii, L. monocytogenes, Included are L. seeligeri, L. murrayi, and L. welshimeri.

In one embodiment the bacterial infection is a respiratory tract infection. In a further embodiment, the infection is a resistant bacterial infection, eg one of the infections provided above. A patient treatable by the methods provided herein, in one embodiment, has been diagnosed with a community-acquired respiratory tract infection, eg, pneumonia. In one embodiment, the bacterial infection treated in pneumonia patients is a S. pneumoniae infection. In another embodiment, the bacterial infection treated in pneumonia patients is Mycoplasma pneumoniae or Legionella species. In another embodiment, in a pneumonia patient the bacterial infection is penicillin resistant, eg, penicillin-resistant S. pneumoniae.

The bacterial infection, in one embodiment, is a hospital acquired infection (HAI) or another health care facility, e.g., nursing home, rehabilitation facility, provided in an outpatient clinic, etc.; Such infections are also called nosocomial infections. In further embodiments, the infection is a respiratory tract infection or a skin infection. In one embodiment, the HAI is pneumonia. In a further embodiment, the pneumonia is due to S. aureus, eg MRSA.

The inhalation delivery device employed in embodiments of the methods provided herein may be a nebulizer, dry powder inhaler (DPI), metered dose inhaler (MDI), or any other known to those of ordinary skill in the art. It can be any suitable inhalation delivery device. The device can comprise and be used to deliver a single dose of the composition, or the device can be comprised and used to deliver multi-doses of the composition of the invention. be able to.

According to one embodiment, the dry powder particle composition is used in a metered dose inhaler (MDI), dry powder inhaler (DPI), atomizer, nebulizer or to provide glycopeptide delivery to a patient in need thereof. It is delivered via a liquid dose instillation (LDI) technique. For inhalation therapy, those skilled in the art will appreciate that the compositions are particularly suitable for delivery via DPIs when hollow and porous microparticle compositions are employed. Conventional DPIs include powdered formulations and devices in which a predetermined dose of drug, either alone or blended with lactose carrier particles, is delivered as a dry powder aerosol for inhalation.

The drug is formulated in such a way that it readily disperses into discrete particles having an MMD between 0.5 and 20 μm, e.g., from 0.5-5 μm, and a median aerodynamic particle diameter (mass It is further characterized by an aerosol particle size distribution less than the median aerodynamic diameter (MMAD), and in some embodiments less than 5.0 μm. The MMAD of the powder will characteristically range from about 0.5-10 μm, from about 0.5-5.0 μm, or from about 0.5-4.0 μm.

The powder is moved either by suction or by some external delivery force, such as pressurized air. Examples of DPIs suitable for application of the particulate compositions of the present invention are US Pat. No. 01/00263, the disclosures of each of which are incorporated by reference in their entireties for all purposes. DPI formulations are typically packaged in single dose units, such as those disclosed in the aforementioned patents, or they are capable of metering multiple doses by manual transfer of the dose to the device. Adopt a reservoir system.

The compositions disclosed herein can also be applied to the patient's nasal or pulmonary airways via aerosolization, such as by a metered dose inhaler (MDI). Breath activated MDIs are also compatible with the methods provided herein.

In addition to the foregoing embodiments, the compositions disclosed herein can be delivered to a patient in need thereof via a nebulizer, such as those disclosed in PCT International Publication No. 99/16420. The disclosure is hereby incorporated by reference in its entirety to provide an aerosolized medicament that can be administered to a patient's pulmonary airways. Nebulizer-type inhalation delivery devices may contain the compositions of the invention as a solution, usually an aqueous solution, or suspension. For example, a prostacyclin (also called prostacyclin) compound or composition can be suspended in saline and loaded into an inhalation delivery device. In producing a nebulized spray of a composition for inhalation, the nebulizer delivery device can be ultrasonic, compressed air, other gas, electronic or mechanical (e.g., vibrating mesh or aperture plate). can be driven to Vibrating mesh nebulizers produce fine particles, low velocity aerosols, and nebulize therapeutic solutions and suspensions at higher velocities than conventional jet or ultrasonic nebulizers. Therefore, treatment duration can be shortened with vibrating mesh nebulizers compared to jet or ultrasonic nebulizers. Vibrating mesh nebulizers suitable for use in the methods described herein include Philips Respironics I-Neb ^(R) (I-Neb), Omron MicroAir, Nektar Aeroneb ^(R) ( Nectar Aeroneb), and Pari eFlow ^(R) .

Nebulizers can be of portable and handheld (also called hand-held) design and can be equipped with a self contained electrical unit. A nebulizer device may include a nozzle, which has two matching outlet channels of defined opening size through which the liquid formulation can be accelerated. This results in two-stream impaction and atomization of the formulation. Nebulizers are inhaled by forcing a liquid preparation through a multiple orifice nozzle of defined aperture size(s) (used to indicate that there can be more than one). A mechanical actuator may be used to generate an aerosol of the pharmaceutical formulation. A single dose nebulizer design may employ a blister pack containing a single dose of the formulation.

In the present invention, a nebulizer may be employed, for example, to ensure optimal particle sizing for particle positioning within the lung membranes.

Upon nebulization, the atomized composition (also called "aerosolized composition") is in the form of aerosolized particles. Aerosolized compositions can be characterized by the particle size of the aerosol, for example, by measuring the "median aerodynamic diameter" or "fine particle fraction" associated with the aerosolized composition. "Median Aerodynamic Diameter" or "MMAD" is normalized with respect to the aerodynamic separation of aqueous aerosol droplets and impactor measurements, e.g. the Andersen Cascade Impactor ( ACI) or Next Generation Impactor (NGI). In one embodiment, the gas flow rate is 8 liters per minute for ACI and 15 liters per minute for NGI.

"Geometric standard deviation" or "GSD" is a measure of the spread of the aerodynamic particle size distribution. Low GSDs are characterized by a narrow droplet size distribution (uniformly sized droplets), which is beneficial for directing the aerosol to the respiratory system. The average droplet size of atomized compositions provided herein, in one embodiment, is less than or about 1 μm to about 5 μm, and 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2, or about It has a GSD in the range of 1.5 to about 2.2.

As used herein, "fine particle fraction" or "FPF" refers to the fraction of an aerosol having particle sizes less than 5 μm in diameter as measured by cascade impaction. FPF is usually expressed as a percentage.

In one embodiment, the atomized composition has a median aerodynamic diameter (MMAD) of from about 1 μm to about 5 μm, or from about 1 μm to about 4 μm, or from about 1 μm to about 3 μm, or from about 1 μm to about 2 μm; Measured with the Anderson Cascade Impactor (ACI) or Next Generation Impactor (NGI). In another embodiment, the MMAD of the atomized composition is about 5 μm or less (also referred to as about 5 μm or less), about 4 μm or less, about 3 μm or less, as measured by cascade impaction, e.g., by ACI or NGI less than or equal to about 2 μm, or less than or equal to about 1 μm.

In one embodiment, the MMAD of the aerosol of the pharmaceutical composition is less than about 4.9 μm, less than about 4.5 μm, less than about 4.3 μm, less than about 4.2 μm, less than about 4.1 μm, less than about 4.0 μm as measured by cascade impaction less than or less than about 3.5 μm.

In one embodiment, the MMAD of an aerosol of the pharmaceutical composition is about 1.0 μm to about 5.0 μm, about 2.0 μm to about 4.5 μm, about 2.5 μm as measured by cascade impaction (e.g., by ACI or NGI) to about 4.0 μm, about 3.0 μm to about 4.0 μm or about 3.5 μm to about 4.5 μm.

In one embodiment, the FPF of the aerosolized composition is greater than or equal to about 50% (also referred to as greater than or equal to about 50%) as measured by ACI or NGI and is about 60% as measured by ACI or NGI. % or greater, or approximately 70% or greater as measured by ACI or NGI. In another embodiment, the FPF of the aerosolized composition is from about 50% to about 80%, or from about 50% to about 70%, or from about 50% to about 60%, as measured by NGI or ACI.

In one embodiment, a metered dose inhaler (MDI) is employed as an inhalation delivery device for the compositions of the present invention. In a further embodiment, the prostacyclin compound is suspended in a propellant (eg, hydrofluorocarbon) prior to loading into the MDI. The basic structure of the MDI includes metering valves, actuators, and containers. A propellant is used to release the formulation from the device. The composition may consist of particles of defined size suspended in a pressurized propellant(s) liquid, or the composition may be in solution or suspension in a pressurized liquid propellant(s). can. The propellants used are primarily atmospheric friendly hydrofluorocarbons (HFCs) such as 134a and 227. The inhalation system device may deliver a single dose, for example via a blister pack, or it may be designed for multiple doses. The pressurized metered dose inhaler of the inhalation system can be breath actuated to deliver precise doses of lipid-containing formulations. To ensure dosing accuracy, formulation delivery may be programmed via the microprocessor to occur at certain points in the inhalation cycle. MDIs may be portable and handheld.

In one embodiment, a dry powder inhaler (DPI) is employed as an inhalation delivery device for the compositions of the present invention.

In one embodiment, the DPI is from about 1 μm to about 10 μm, or from about 1 μm to about 9 μm, or from about 1 μm to about 8 μm, or from about 1 μm to about 7 μm, or from about 1 μm to about 1 μm, or from about 1 μm to about 1 μm in diameter, as measured by NGI or ACI. Particles are produced having an MMAD of about 6 μm, or about 1 μm to about 5 μm, or about 1 μm to about 4 μm, or about 1 μm to about 3 μm, or about 1 μm to about 2 μm. In another embodiment, the DPI is from about 1 μm to about 10 μm, or from about 2 μm to about 10 μm, or from about 3 μm to about 10 μm, or from about 4 μm to about 10 μm, or from about 5 μm to about 5 μm, as measured by NGI or ACI. Particles are produced having an MMAD of 10 μm, or from about 6 μm to about 10 μm, or from about 7 μm to about 10 μm, or from about 8 μm to about 10 μm, or from about 9 μm to about 10 μm.

In one embodiment, the MMAD of particles produced by DPI is about 3 μm or less, about 2 μm or less, or about 1 μm or less.

In one embodiment, each application includes 1 to 5 doses (puffs, also called puffs) from the DPI, e.g., 1 dose (1 puff), 2 doses (2 puffs), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 puffs). In one embodiment, the DPI is small and portable by the patient.

In one embodiment, the MMAD of particles produced by DPI is less than about 9.9 μm, less than about 9.5 μm, less than about 9.3 μm, less than about 9.2 μm, less than about 9.1 μm, about 9.0 as measured by NGI or ACI less than about 8.5 μm, less than about 8.3 μm, less than about 8.2 μm, less than about 8.1 μm, less than about 8.0 μm, less than about 7.5 μm, less than about 7.3 μm, less than about 7.2 μm, less than about 7.1 μm, about 7.0 Less than about 6.5 μm, less than about 6.3 μm, less than about 6.2 μm, less than about 6.1 μm, less than about 6.0 μm, less than about 5.5 μm, less than about 5.3 μm, less than about 5.2 μm, less than about 5.1 μm, about 5.0 μm less than about 4.5 μm, less than about 4.3 μm, less than about 4.2 μm, less than about 4.1 μm, less than about 4.0 μm, or less than about 3.5 μm.

In one embodiment, the MMAD of particles produced by DPI is about 1.0 μm to about 10.0 μm, about 2.0 μm to about 9.5 μm, about 2.5 μm to about 9.0 μm, about 3.0 μm to about 9.0 μm, about 3.5 μm to about 8.5 μm or from about 4.0 μm to about 8.0 μm.

In one embodiment, the FPF of the prostacyclin particle composition produced by DPI is greater than or equal to about 40% (also referred to as greater than or equal to about 40%) as measured by ACI or NGI; About 50% or more as measured, or about 60% or more as measured by ACI or NGI, or about 70% or more as measured by ACI or NGI. In another embodiment, the FPF of the aerosolized composition is from about 40% to about 70%, or from about 50% to about 70%, or from about 40% to about 60%, as measured by NGI or ACI.

The invention is further illustrated by reference to the following examples. However, it should be noted that these examples, like the embodiments described above, are illustrative and should not be construed as limiting the scope of the invention in any way.
Example 1 - Synthesis of glycopeptide derivatives via reductive amination

Glycopeptide derivatives were prepared as follows. A further synthetic scheme is provided in FIG.

Anhydrous DMF and DIPEA were added to a reaction vessel equipped with temperature control and agitation. The resulting solution was heated to 65° C. with stirring and vancomycin HCl or telavancin HCl was added slowly in portions. Heating was continued until all the vancomycin HCl or telavancin HCl was dissolved (5-10 minutes).

After cooling the beige solution, a solution of the desired aldehyde dissolved in DMF was added over 5-10 minutes. The resulting solution was allowed to stir overnight, typically producing a clear red-yellow solution. MeOH and TFA were introduced and stirring continued for at least another 2 hours. At the end of the stirring period, the imine-forming reaction mixture was analyzed by HPLC, which was characteristically typical. Borane tert-butylamine complex was added in portions and the reaction mixture was stirred at ambient temperature for an additional 2 hours, after which in-process HPLC analysis of the reaction mixture showed almost quantitative reduction of intermediate imine groups. After the reaction is complete, the reaction mixture is subjected to reverse-phase C18 column chromatography (Phenomenex Luna 10uM PREP C18(2) using a gradient of water and acetonitrile each containing 0.1% (v/v) TFA. ) 250×21.2 mm column). Fractions were evaluated using HPLC and appropriate fractions containing the target product were then pooled together for product separation via lyophilization. A typical product was isolated as a fluffy white solid. The procedure is shown below in Scheme 1 using vancomycin HCl as a representative starting compound.
Example 2 - Synthesis of Vancomycin Derivative RV40 (Compound 40)

General Synthesis: A suitable reaction solvent (DMF or DMA) and an organic base (typically DIPEA) were added to a temperature-controlled reaction vessel equipped with an overhead stirrer. The temperature was raised to approximately 60°C and vancomycin HCl was added. The warm reaction mixture was stirred at elevated temperature for approximately 20 minutes, at which point all vancomycin HCl dissolved and the reaction mixture was allowed to warm to room temperature. To the reaction mixture is then added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate (N-Fmoc-N-decylaminoacetaldehyde) dissolved in an appropriate reaction solvent (DMF or DMA). rice field. The reaction mixture was stirred overnight with an overhead stirrer, at which point a suitable reducing agent, acid catalyst (eg TFA), and protic solvent (eg MeOH) were added. The reaction mixture was stirred with an overhead stirrer at room temperature for approximately 2 hours, at which point the solvent volume was reduced by half via rotary evaporation. An organic base was then added to the concentrated reaction mixture to remove the FMOC protecting group and produce the crude product (compound 40, also called "RV40", see also Table 1). The solvent was then evaporated by rotary evaporation and the crude material was dry-packed using C18 silica and reverse phase C18 flash chromatography to separate products with >97% purity. refined through Solvent was removed from the purified material using a combination of techniques including rotary evaporation, freeze-drying, and spray-drying to give the product (compound 40 or RV40) as a white powder, typically in overall yields of 40%. Produced at -75%. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylacetamide or combinations thereof. Suitable organic bases include N,N-diisopropylethylamine or trimethylamine. Suitable reducing agents include NaBH4, _NaBH3CN , borane _- pyridine complexes, or borane- ^{tertbutylamine} complexes. Suitable organic bases for FMOC deprotection include piperidine, methylamine, and ^{tertbutylamine} .

Salt Form: Control over the salt form and associated counterion for the alkyl-vancomycin derivatives was controlled by varying the acid species used during flash chromatography. Lactic acid, acetic acid, HCl, and TFA salts were prepared. To separate the free base derivative of the alkylvancomycin derivative, the pH of the purified material is adjusted between 7-8 to induce precipitation; the purified free base material is then filtered, rotary evaporated and frozen. Collected by drying or spray drying.

One synthetic scheme to arrive at compound 40 (RV40) is provided in Figure 2 (top). Here, a jacketed 1 L reaction vessel was equipped with an overhead stirrer and connected to a recirculating water bath regulated at 65°C. N,N-Dimethylformamide (75 mL) and DIPEA (640 μL, 3.7 mmol, 2.0 equiv) were added to a warm reaction vessel. The solvent was allowed to stir for 20 minutes and warmed to 65° C., at which point vancomycin HCl (2.70 g, 1.8 mmol, 1.00 eq) was added to the reaction mixture. Once all vancomycin HCl was dissolved, the temperature was lowered to 25° C. and 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate (890 mg) dissolved in N,N-dimethylformamide (20 mL) was added. , 2.1 mmol, 1.15 eq.) was added. The reaction mixture was allowed to stir at 25° C. for 18 hours. _NaBH3CN (330 mg, 5.3 mmol, 2.89 eq), MeOH (75 mL), and TFA (3.0 mL, 5.5 mmol, 3.00 eq) were then added to the reaction mixture. The reaction mixture was allowed to stir at RT (room temperature) for 3 hours, at which point the solvent volume was reduced by half by rotary evaporation. Piperidine (360 μL, 3.7 mmol, 2.00 eq) was then added to the concentrated reaction mixture with stirring. Reaction progress was monitored by HPLC. Once HPLC analysis indicated complete deprotection, the solvent was removed from the reaction mixture under reduced pressure to yield the crude product (compound 40) as an off-white solid. The crude material was dry packed using C18 silica and purified via reverse phase C18 flash chromatography to isolate the product with >97% purity.
Example 3 - Synthesis of Vancomycin Derivative RV40 (Compound 40)

General Synthesis: A suitable reaction solvent (DMF or DMA) and an organic base (typically DIPEA) were added to a temperature-controlled reaction vessel equipped with an overhead stirrer. The temperature was raised to approximately 60°C and vancomycin HCl was added. The warm reaction mixture was stirred at elevated temperature for approximately 20 minutes at which point all vancomycin HCl dissolved and the reaction mixture was allowed to warm to room temperature. To the reaction mixture is then added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate (N-Fmoc-N-decylaminoacetaldehyde) dissolved in an appropriate reaction solvent (DMF or DMA). rice field. The reaction mixture was stirred overnight with an overhead stirrer. A protic solvent (eg, MeOH) and an acid catalyst (eg, TFA) are added to the reaction mixture, and the reaction mixture is stirred for 15 minutes prior to addition of a suitable reducing agent (eg, borane tertbutylamine complex). I left it.

The reaction mixture was stirred with an overhead stirrer at room temperature for approximately two hours, at which time an organic base (eg tertbutylamine) was added to remove the FMOC protecting group. The temperature was raised to 55°C and the mixture was left stirring for 2 hours. The solvent was then evaporated by rotary evaporation and the crude material was dry packed using C18 silica and purified via reverse phase C18 flash chromatography to isolate products with >97% purity. . Solvent was removed from the purified material using a combination of techniques including rotary evaporation, freeze-drying, and spray-drying to obtain the product (RV40) as a white powder, typically in an overall yield of 75%. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylacetamide or combinations thereof. Suitable organic bases include N,N-diisopropylethylamine or trimethylamine. Suitable reducing agents include NaBH4, _NaBH3CN , Borane _- pyridine complexes, or Borane- ^{tertbutylamine} complexes. Suitable organic bases for FMOC deprotection include piperidine, methylamine, and ^{tertbutylamine} .

Salt Forms: Salt forms and associated counterion controls for the alkyl-vancomycin derivatives were controlled by varying the acid species used during flash chromatography. Lactate, Acetate, HCl, and TFA salts were prepared. To isolate the free base derivative of the vancomycin derivative, the pH of the purified material is adjusted between 7-8 to induce precipitation; the purified free base material is then filtered, rotary evaporated, lyophilized, or Collected by spray drying.
One synthetic scheme to arrive at compound 40 (RV40) is provided in FIG. 2, bottom, and is described in further detail below. DMF (50 mL) and DIPEA (1.17 mL, 6.73 mmol, 2.00 equiv) were added to a 400 mL reaction vessel equipped with an overhead stirrer, thermometer, and pH meter. The reaction mixture was heated to 55° C. at which point vancomycin HCl (5.0 g, 3.37 mmol, 1.0 equiv) was added. The mixture was stirred at 55°C for approximately 15 minutes or until all the vancomycin had dissolved, at which point the temperature was reduced to 25°C. To the reaction mixture was added a solution of N-Fmoc-decylaminoacetaldehyde (1.63 g, 3.87 mmol, 1.15 eq) dissolved in DMF (16.32 mL). The reaction mixture was allowed to stir at 25° C. for 18 hours. MeOH (14.0 mL) and TFA (1.03 mL, 13.46 mmol, 4.00 eq) were added to the reaction mixture and the mixture was allowed to stir at 25° C. for 15 min, at which point borane tert-butylamine complex (294 mg, 3.37 mmol) , 1.0 eq.) was added. The reaction mixture was allowed to stir at 25°C for 2 hours at which point tert-butylamine (4.24 mL, 40.38 mmol, 12.0 eq) was added and the temperature was raised to 55°C. The reaction mixture was allowed to stir at 55° C. for 2 hours. C18-functionalized silica gel was then added to the reaction mixture and the solvent was removed under reduced pressure. Dry-packed material was purified using reverse-phase C18 flash chromatography ⁽ Biotage® SNAP-KP-C18-HS column).
Example 4 - Preparation of monolactate salt of RV40

A 3-L, three-necked flask was equipped with a mechanical stirrer (also referred to as stirrer), nitrogen inlet, condenser (also referred to as condenser) and addition funnel. Anhydrous DMF (900 mL) and DIPEA (21.06 mL, 0.12 mol) were loaded. The resulting solution was heated to 55-60° C. and vancomycin.HCl (90.0 g, 0.06 mol) was added portionwise. Heating was continued until all the vancomycin.HCl was dissolved (15-30 minutes). The beige solution was allowed to cool to ambient temperature, then a solution of N-FMOC-N-decylaminoacetaldehyde (29.34 g, 0.069 mol) and DMF (293.4 mL) was added via addition funnel over 5-10 minutes. added. The obtained solution was allowed to stir overnight to give a clear red-yellow solution. In-process HPLC analysis of the reaction mixture at the end of the stirring period was typical. MeOH (252 mL) and TFA (18.54 mL, 0.24 mol) were introduced and stirring continued for at least 2 more hours. At the end of the stirring period, the imine-forming reaction mixture was analyzed by HPLC which was characteristically typical. Borane tert-butylamine complex (5.28 g, 0.61 mol) was added in portions and the reaction mixture was stirred at ambient temperature for an additional 2 hours, after which time in-process HPLC analysis of the reaction mixture indicated 3 unreacted vancomycin. A nearly quantitative reduction of the imine groups of the intermediate with less than % remaining was shown. Tert-Butylamine (76.32 mL, 0.73 mol) was added via addition funnel and the resulting reaction was heated to 55°C. Stirring was continued at 55° C. and the progress of the deprotection reaction of the FMOC group was monitored by HPLC.

After the reaction is complete (about 2 hours), remove the heating and add C18 silica gel (C-18 (17% carbon) 60A, 40-63 μm, 270 g) and rotavap the mixture. Concentrate on a rotary evaporator at 52° C./15 torr until a free-flowing solid of C-18 silica with adsorbed crude RV40 is obtained (3-7 hours). The C-18 silica adsorbed crude RV40 (compound 40) was split into three equal portions and each part-lot was loaded onto a Biotage SNAP ULTRA C18 1850 g cartridge (Biotage HP-Sphere C18) using a gradient of water and acetonitrile. 25 μm) Biotage chromatography, each containing 0.1% (v/v) 85% L-(+)-lactic acid solution in water, and 240 mL fractions are collected. Each part lot required ~ (also called approximately) 50 liters of eluent. After each Biotage run, the C-18 column was conditioned for the next run by passing 60 liters of methanol through it. Fractions were evaluated using HPLC and then pertinent fractions containing RV40were pooled together for product separation via lyophilization.

Lyophilization provided RV40 lactate as a white solid. RV40 lactate lyophilized at this point typically contained excess lactic acid and also contained lactic acid-related impurities resulting from its self-condensation reaction. The RV40 lactate isolated from this experiment was similarly isolated frozen to form a composite batch of RV40 lactate totaling 105 g (lot 637-140A). Combined with two other batches of dry RV40 lactate. Excess lactic acid and its related impurities present in the above composite batch of RV40 lactate are removed via trituration with THF and then the final tritate (RV40 monolactate salt ) is subjected to re-lyophilization to remove residual THF entrapped; both steps are described below.

A 5 L three-necked flask was equipped with a mechanical stirrer, nitrogen inlet, and condenser. RV40 lactate salt (105 g) and inhibitor-free anhydrous THF (1 L) were loaded. The resulting mixture was stirred under nitrogen. After stirring overnight, the resulting mixture was filtered using a medium frit Buchner filter funnel. The filtered cake was washed with THF (250 mL). The filter cake was dried on the filter funnel by pulling vacuum under nitrogen. After drying for 5 hours, the cake was analyzed by 1H NMR for residual level of lactic acid measured as 3.5 equivalents. The trituration process with THF was repeated two more times after which the isolated product was determined to contain an estimated 1 equivalent of lactic acid/lactate and THF. The isolated material was re-lyophilized to remove residual THF as follows:

The above THF-ground material was first dissolved in aqueous acetonitrile (3:1 water:acetonitrile) at a concentration of 8.1 mL per gram and then lyophilized in batches using multiple flasks. Typically, about 10-12 grams (maximum) of material was charged into each 2 L flask followed by aqueous acetonitrile (125 mL) to prepare the lyophilized solution. At the end of lyophilization and drying, the product was analyzed for THF levels by NMR to determine if lyophilization needed to be repeated. In the present case, the contents of each flask were lyophilized once again (after redissolving in 125 mL aqueous acetonitrile) when no residual THF was detectable by NMR. The final lyophilized product at this point contained an average of 0.8 wt% acetonitrile as estimated by NMR. The contents of each flask were ground into smaller particles using a spatula and then placed on a high vacuum pump to remove acetonitrile. No further drop in acetonitrile levels was observed after 56-60 hours on the vacuum pump. The contents of each flask were combined to provide a total of 74.3 g (35.5% yield based on total conversion of 180 g of vancomycin.HCl) of the combined batch of RV40 monolactate salt as a white solid that was >99% by HPLC. It was found to be area % pure and contained one equivalent of lactate as determined by 1HNMR (DMSO-d6) analysis. Water content in the product was found at 5.6 wt% as determined by KF analysis.
Example 5 - Synthesis of Vancomycin Derivative RV79

A synthetic scheme to arrive at the glycopeptide derivative RV79 is described below and also provided in FIG. Anhydrous DMF (20 mL) and DIPEA (0.20 mL) were added to a 40 mL vial equipped with a stir bar. The obtained solution was heated to 65° C. in an incubating shaker and vancomycin.HCl (700 mg, 0.462 mmol) was added slowly in small portions. Heating was continued until all vancomycin.HCl was dissolved (5-10 minutes). The beige solution was allowed to cool to room temperature, at which point 4'-chloro-biphenyl-4-carbaldehyde (0.1 g, 0.462 mmol) was added to the reaction mixture. The reaction mixture was allowed to stir overnight. MeOH (1.5 mL) and TFA (0.14 mL, 1.8 mmol) were introduced and stirring continued for at least 2 more hours. Borane tert-butylamine complex (40 mg, 0.46 mmol) was added in portions and the reaction mixture was stirred at ambient temperature for an additional 2 hours. After completion of the reaction, the reaction mixture was subjected to reverse phase C18 column chromatography (Phenomenex Luna 10 uM PREP C18(2) 250×21.2) using a gradient of water and acetonitrile each containing 0.1% (v/v) TFA. mm column). Fractions were evaluated using HPLC, and appropriate fractions containing RV79 were then pooled together for product separation via lyophilization. The target compound, RV79 (81.2 mg, 0.05 mmol, 10% overall yield) was obtained as a white solid with >97% purity (by HPLC). The reaction scheme is shown in Figure 3.
Example 6 - Synthesis of Alkyl-vancomycin Derivatives

Alkylvancomycin derivatives were prepared according to the procedure disclosed in Nagarajan et al., with some modifications (Nagarajan et al. (1989). The Journal of Antibiotics 42(1), pp. 63-72, see incorporated herein in its entirety for all purposes by).

A general synthesis for alkylvancomycin derivatives is shown in FIG. Briefly, vancomycin HCl, a suitable reaction solvent, an organic base, and a suitable aldehyde were added to a temperature-controlled reaction vessel. The reaction mixture was stirred at elevated temperature with an overhead stirrer and the progress of the reaction was monitored via HPLC watching for vancomycin consumption and imine formation. Appropriate reducing agent, acid catalyst (TFA), and protic solvent (MeOH) were then added to the reaction vessel. The reaction mixture was stirred with an overhead stirrer for approximately 2 hours. The reaction mixture was then either poured into water or the solvent was removed under reduced pressure to induce precipitation of the alkylvancomycin derivative.

The crude material was dissolved in a suitable mobile phase and purified via preparative chromatography. Solvent was removed from the purified material using a combination of techniques including rotary evaporation, freeze-drying, and spray-drying to produce the vancomycin alkyl derivative as a white powder, typically in 40-60% overall yield. . Suitable solvents include N,N-dimethylformamide or N,N-dimethylacetamide. Suitable organic bases include N,N-diisopropylethylamine or trimethylamine. Suitable reducing agents include NaBH4, _NaBH3CN , borane _- pyridine complexes, or borane- ^{tertbutylamine} complexes.

Synthesis of N-decylvancomycin (compound 5): A synthetic route to compound 5, decylvancomycin, is provided in FIG. A jacketed 1 L reaction vessel was equipped with an overhead stirrer and connected to a recirculating water bath regulated at 65°C. N,N-Dimethylacetamide (160 mL) and DIPEA (6.8 mL, 39.0 mmol, 2.92 eq) were added to a warm reaction vessel and the solvent was allowed to stir for approximately 20 minutes. Vancomycin HCl (19.8 g, 13.38 mmol, 1.00 equiv) was added to the reaction vessel when the solvent temperature reached 65°C. 1-Decanal (2.54 mL, 13.50 mmol, 1.01 eq) was added to the reaction vessel and the reaction mixture was allowed to stir at 65° C. for 2 hours. _NaBH3CN (2.31 g, 36.77 mmol, 2.75 eq), MeOH (100 mL), and TFA (3.1 mL, 40.48 mmol, 3.03 eq) were then added to the reaction mixture. The reaction mixture was allowed to stir for 2 hours while cooling to room temperature. The reaction mixture was then poured into acetonitrile (1 L) to induce precipitation. The decant was removed and the remaining off-white slurry was centrifuged and decanted to remove excess solvent and produce a slurry containing N-decylvancomycin and unreacted vancomycin. Crude N-decylvancomycin was dissolved in 30:70 acetonitrile: _H2O with 0.05% HOAc and purified using reverse-phase C18 preparative HPLC. Pure fractions were subjected to rotary evaporation to remove organics and flash frozen and lyophilized to isolate purified N-decylvancomycin as a fluffy white powder.
Example 7 - Synthesis of chloroeremomycin derivative RV79

A solution of copper (II) acetate in chloroeremomycin and MeOH was added to a 20 mL scintillation vial equipped with a stir bar. The reaction mixture was stirred at room temperature until the chloroeremomycin dissolved. To the reaction mixture was then added the appropriate aldehyde and sodium cyanoborohydride as a 1M solution in THF. The reaction mixture was transferred to an incubated shaker set at 45° C. and reaction progress was monitored by HPLC. In some cases it was necessary to add additional aliquots of the aldehyde reagent. The reaction mixture was left shaking overnight at 45°C. The reaction mixture was cooled to RT and sodium borohydride was added to convert residual aldehyde reagent to the corresponding alcohol. The pH was adjusted to between 7-8 using either acetic acid or 0.1 M NaOH, and volatile solvents were removed by gently heating and blowing N ₂ (g). Acetonitrile was added to the reaction mixture to precipitate the crude product as an off-white solid. The reaction mixture was centrifuged and the liquid decanted. The solids dissolved in 10% MeCN/ _H2O with 0.1% phosphoric acid to decomplex the copper, at which point the solution turned temporarily purple and then yellowish. . Preparative HPLC was used to purify the final product and LCMS was used to confirm the identity and purity of the compound.

A diagram of the reaction is provided in FIG. 1, bottom.
Example 8 - C-Terminal Modification of Glycopeptide Derivatives

A LPGC derivative, a 1:1 solution of DMF:DMSO, and DIPEA were added to a round bottom flask equipped with a stir bar. HBTU and a suitable amine (eg, 3-(dimethylamino)-1-propylamine) were then added to the reaction mixture. Reaction progress was monitored by HPLC. Upon completion, the reaction was quenched by adding 1:1 _H2O :MeOH. The crude material was then purified using reverse phase C18 preparative HPLC. Purified fractions were lyophilized to yield the target product, typically as a white fluffy powder in moderate yield and high purity.
Example 9 - Resorcinol-Like Modification of Glycopeptide Derivatives

(Aminomethyl)phosphoric acid, water, and DIPEA were added to a round bottom flask equipped with a stir bar. The reaction mixture was allowed to stir at room temperature for 15 minutes. Acetonitrile and formaldehyde were then added to the reaction mixture as a 37% solution in _H2O . The reaction mixture was allowed to stir for an additional 15 minutes at which time the glycopeptide derivative and additional DIPEA were added. The progress of the reaction was carefully monitored using HPLC. Upon completion, the reaction mixture was purified using reverse phase C18 preparative HPLC. The purified fractions were lyophilized to yield the target product as a white fluffy powder.
Example 10 - Minimum Inhibitory Concentration (MIC) of Glycopeptide Derivatives

例11-グラム陽性細菌に対するグリコペプチド剤のインビトロ活性 MIC testing (MIC test): Glycopeptide compounds were dissolved in 100% DMSO. Minimum drug inhibitory concentrations (MICs) of compounds against quality control strain ATCC 29213 (MSSA) and MRSA isolate ATCC BAA-1556 using CLSI-guided broth susceptibility testing In vitro activity was determined to measure Minimum inhibitory concentrations MICs are outlined in Table 2. Glycopeptides are defined as compounds of formula (I) and their respective R ¹ , R ² , R ³ and R ⁴ groups. In Table 2, X is -O- for each compound.

Example 11 - In Vitro Activity of Glycopeptide Agents Against Gram-Positive Bacteria

Susceptibility of a wide variety of Staphylococcus aureus (also known as Staphylococcus aureus, Staphylococcus aureus, etc.) was evaluated, including reference methicillin-resistant (MRSA) and vancomycin-intermediate (VISA) isolates to various antibiotic compounds.

Broth microdilution MIC studies are performed according to guidelines from the Clinical and Laboratory Standards Institute (CLSI; 1, 2) and as comparators. Included were telavancin (TLV), vancomycin (VAN), tigecycline (TGC), and linezolid (LNZ). In addition, susceptibility of other Gram-positive bacteria (Enterococci, Streptococci, and Clostridium difficile) to test agents and comparators was also determined.
material and method

test compound. Table 3 below details the six test agents and comparators.

isolate. Test organisms were originally from clinical sources, the American Type Culture Collection (ATCC, Manassas, VA), and the Network on Antimicrobial Resistance in S. aureus. Network for Resistance) (NARSA; BEI Resources (NARSA; BEI Resources), Manassas, VA). After receipt, the organisms were subcultured on appropriate agar media. Following incubation, colonies were harvested from these plates and cell suspensions were prepared and frozen at -80°C with cryoprotectant. The day before the assay, cryopreserved isolates were plated on Trypticase Soy Agar containing 5% sheep blood (Remel, Lenexa, KS, Kansas; Lot No. (lot number) 964323) and incubated in ambient atmosphere at 35°C overnight, then incubated overnight at 35°C in 5% CO ₂ Streptococci and Brucella agar (Brucella Agar) (Becton Dickinson, Sparks, Md.; Lot No. 6168880) and anaerobically incubated at 35°C for 48 hours, excluding C. difficile did.

The following S. aureus isolates and associated phenotypes were evaluated against the aforementioned antibiotics (Table 4).

S. aureus ATCC 29213 was included during testing of S. aureus for quality control purposes (Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement. Test Performance Criteria: Section 27 Information Supplement.) CLSI document M100-S27.CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2017;2017;CLSI.Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard-Tenth Edition. 10th ed.) CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087-1898 USA, 2015).

A summary of a subset of MRSA strains is also provided in Table 5.

With respect to MRSA strains (Table 5), compound 40 (RV40) was found to be more active than the respective comparators by the factors provided in Table 6.

A summary of the subset of Gram-positive strains other than those of S. aureus species is provided in Table 7 below. Blank entries indicate that the respective antibiotic was not tested against the respective organism.

test medium. The medium employed for the MIC assay was cation-adjusted Mueller-Hinton Broth (MHBII; BD; Lot No. 6117994), but supplemented Brucella Broth o C. difficile tested in broth, brucella broth, etc.) (SBB) was excluded. For Streptococcus isolates, MHBII was supplemented with 3% Laked Horse Blood (Cleveland Scientific; Bath, OH; Lot No. 333835). To test C. difficile, Brucella Broth (BD; Lot No. 6155858) was supplemented with vitamin K (Sigma, St. Louis, MO; Lot No. 108K1088), hemin (Sigma, Lot No. SLB14685V), and 5% Laked Added Horse Blood. Test media were prepared fresh on each day of testing and tested according to CLSI (Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement. CLSI document M100-S27, CLSI, 950 West Valley). Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2017；CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne , Pennsylvania 19087-1898 USA, 2015) and for testing of oritavancin, compound 40 and compound 5, were supplemented with 0.002% polysorbate-80 (v/v).

test procedure. MIC values are obtained from CLSI (Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement. CLSI document M100-S27. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2017) using the liquid microdilution procedure described by Automated liquid handlers (Multidrop 384, Labsystems, Helsinki, Finland; Biomek 2000 and Biomek FX, Beckman Coulter, Fullerton (Fullerton) Calif.) was used to perform serial dilutions and liquid transfers.

To prepare a drug mother plate that provides serial drug dilutions to replicate daughter plates, add 150 μL to wells in columns 2-12 of a standard 96-well microdilution plate (Costar 3795). Diluent was filled for each row of drugs. Test articles and comparator compounds (300 μL at 100× the highest concentration to be tested) were dispensed into appropriate wells in row 1. Two-fold serial dilutions were then performed on the mother plate from row 1 to row 11 using the Biomek 2000. Wells in row 12 contained no drug and served as organism growth control wells for the assay.

Daughter plates were loaded with 190 μL per well of appropriate test media containing 0.002% polysorbate-80 (v/v) for telavancin, oritavancin, compound 40, and compound 5 using a Multidrop 384. Daughter plates were prepared on a Biomek FX instrument, which transferred 2 μL of drug solution from each well of the mother plate to the corresponding wells of each daughter plate in a single step. Daughter plates for C. difficile were placed in an anaerobic chamber and allowed to reduce for 1 hour prior to inoculation.

A standardized inoculum of each organism was prepared according to the CLSI method (CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087-1898 USA, 2015). Bacterial suspensions were prepared in MHBII (or in the case of C. difficile SBB without blood) to equal the turbidity of a 0.5 McFarland standard. The 0.5 McFarland suspension was further diluted 1:20 (or 1:10 for C. difficile) in the appropriate test medium. Each organism inoculum was dispensed into a sterile reservoir (Beckman Coulter 372788) and a Biomek 2000 was used to deliver 10 μL of standardized inoculum into each well, giving a final test concentration of approximately 5×10 ⁵ CFU/well. Make up to mL. The daughter plate was placed on a Biomek 2000 work surface and work surface reversed, resulting in low to high drug inoculation. For C. difficile, inoculum preparation and daughter plate inoculation were accomplished manually in an anaerobic chamber.

The plates are stacked in 3 layers, covered with a lid on the top plate, placed in a plastic bag, and at 35° C. in ambient atmosphere, approximately 18-20 for telavancin, compound 40, compound 5, oritavancin, linezolid, and tigecycline. hours, or 24 hours for vancomycin, with the exception of C. difficile plates that were anaerobically incubated at 35°C for 48 hours. Following incubation, the microplate was removed from the incubator and viewed from the bottom using a plate viewer. For each test compound, uninoculated solubility control plates for each test vehicle were observed for evidence of drug precipitation. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth. For linezolid, pinpoint trailing was ignored when reading the MIC per CLSI (CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI , 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087-1898 USA, 2015).
result

No precipitation was observed for the comparator during the assay with the uninoculated solubility control. Some precipitation was noted for Compound 40 and Compound 5 at the top concentration tested (64 μg/mL) in MHBII with blood and supplemented Brucella broth, and for Compound 40 (RV40) in HTM. However, this precipitation did not interfere with the reading of MICs. The MICs of the comparators for ATCC quality control organisms were within established CLSI QC ranges (CLSI. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Seventh Informational Supplement. CLSI document M100-S27. CLSI, 950 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-2017.), thus validating the assay.

Observed MIC values for various antibiotics for S. aureus strains are provided in Tables 3-5. These data are also provided in FIGS. Data for 12 MRSA strains are provided in Tables 4-5 and Figures 8 and 9.

Observed MIC values for various antibiotics for Gram-positive strains other than S. aureus are provided in Table 6. Compound 40 was the most potent compound across the Streptococci, Enterococci, and C. difficile test isolates evaluated. The activity observed with compound 40 was 5-fold higher than that of telavancin, a trend consistent with the data observed with S. aureus when compound 40 was 3-fold higher than that of telavancin (Table 1). Both telavancin and compound 40 had potent activity against vancomycin-resistant enterococci (VRE), but MIC values for VRE were elevated compared to vancomycin-susceptible enterococci (VSE) .
Example 12 - MRSA 1556 Biofilm Eradication

vancomycin (Vanc), telavancin (TLV), oritivancin (ORI) and RV40 (compounds of formula (I) or (II) where ^R1 is ( _CH2 )-NH-( _CH2 ) ₉ - _CH3 ) , ^R2 is OH, R3 and ^{R4 are} H, and X is O) were tested for their ability to eradicate MRSA 1556 biofilms.

For biofilm development, cystic fibrosis bronchial epithelial (CFBE) cells seeded in empty 96-well or 24-well plates were incubated with overnight cultures of MRSA 1556. (overnight culture) was inoculated for 6 hours, and then antibiotic treatment was continued for 16 hours. After 16 hours of incubation, planktonic bacteria were removed and biofilms were disrupted by a scraping method and collected for CFU counting. Results are provided in Figure 10 (plastic biofilm) and Figure 11 (cellular biofilm). RV40 significantly killed MRSA 1556 biofilms formed on plastic at 0.3-10 μg/ml compared to telavancin and vancomycin (Fig. 10). RV40 was more effective at abolishing MRSA 1556 biofilms developed in co-culture with CFBE cells with a >3 log CFU/ml reduction at 20 μg/ml compared to vancomycin, telavancin, and oritavancin. (Fig. 11).
Example 13 - In Vivo Activity of Glycopeptide Agents Against MRSA Organisms

Male Sprague Dawley rats (179-200 g) were neutrophilic through a series of cyclophosphamide injections (IP) at 150 mg/kg (days-4) and 100 mg/kg (days-1). Decreased balls. They were then challenged with Methicillin-Resistant Staphylococcus aureus (MRSA) (ATCC-BAA-1556; TPPS 1062) at 8 log10 via intranasal (IN) instillation on study day 0 Infected (also called challenged).

Rats were placed on a CH Technologies 12 Port Module Oral-Nasal Aerosol and Respiratory Exposure Systems (CH Technologies 12 Port Module Oral-Nasal Aerosol and Respiratory Exposure Systems) connected to an Aeroneb Pro nebulizer at 12 and 24 hours post-challenge (post-challenge). Animals were treated with vehicle control (bicine; pH 9.2) or RV40 (compound 40) (in bicine; pH 9.2) via nebulization using a modular oral-nasal aerosol and respiratory exposure system (ONARES). At 36 hours post-challenge lungs were collected for CFU enumeration. Results are shown in FIG.

For the data reported in Figure 13, at 36 hours post-challenge lungs were collected for CFU enumeration. Nebulized drug was performed using the same procedure described for the data in FIG. Results are listed as ΔLog reduction in lung CFU vs. control (FIG. 13).

Using the same animal model from Figure 12, the data in Figure 14 regarding the dose response of inhaled RV40 in reducing pulmonary MRSA CFUs were obtained. Again, animals were treated with drugs 12 and 24 hours after challenge infection. At 36 hours post-challenge lungs were harvested for CFU enumeration. Here, using the same nebulization procedure described for the data in FIG. 12, animals were dosed with RV40 at body weight targets of 1, 2, 5, and 10 mg/kg. Results are listed as ΔLog reduction in lung CFU versus control (FIG. 14). Data are plotted as means and error is SEM.

The same animal model from Figure 12 was used to acquire the data in Figure 15 for prophylactic dosing of inhaled RV40 to reduce pulmonary MRSA CFUs. Here, animals received single doses of nebulized inhaled RV40 (10 mg/kg body weight target) 7, 5, 3, and 1 days before bacterial challenge infection and 0.5 days after bacterial challenge infection. provided. Thirty-six hours after challenge infection, lungs were harvested for CFU enumeration. Dosing was performed using the same nebulization procedure described for the data in FIG. Results are provided in FIG. Data are plotted as geometric means with 95% CI. Statistics are based on one-way ANOVA (p=0.001) with post-hoc Bonferroni multiple comparison test. N=11 for treatment groups on days −7, −5, −3, −1, n=10 for days +0.5, and n=8 for controls.
* * * * * * * *

All documents, patents, patent applications, publications, product descriptions, and protocols cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best manner known to the inventors for making and using the invention. Modifications and variations of the above-described embodiments of the invention are possible without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. Therefore, it is understood that within the scope of the claims and their equivalents, the invention may be practiced other than as specifically described.

Claims (9)

1. A pharmaceutical composition for treating cystic fibrosis characterized by the presence of pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infection in a patient in need thereof, comprising:
The pharmaceutical composition comprises an effective amount of formula (II):

(II)
(In the formula,
^R1 is (CH2 ₎ 2 _- NH-(CH2 ₎ 9 _{- CH3} ;
^R2 is -OH ;
R ³ is H ;
R ⁴ is H ;
X is O)
or a pharmaceutically acceptable salt thereof ,
the pharmaceutical composition is applied to the patient's lungs via a nebulizer, metered dose inhaler or dry powder inhaler;
Pharmaceutical composition. 2. The pharmaceutical composition of claim 1 , comprising an effective amount of the compound of formula (II) above . 2. The pharmaceutical composition of claim 1 , comprising an effective amount of a pharmaceutically acceptable salt of the compound of formula (II) above . 4. The pharmaceutical composition of claim 3 , comprising an effective amount of the lactate, acetate, HCl or trifluoroacetate (TFA) salt of the compound of formula (II) above . 5. The pharmaceutical composition of claim 4 , comprising an effective amount of the lactate salt of the compound of formula (II) above . 6. The pharmaceutical composition of claim 5 , comprising an effective amount of the monolactate salt of the compound of formula (II) above . 7. The pharmaceutical composition of any one of claims 1-6 , applied to the patient's lungs via a nebulizer . 7. The pharmaceutical composition according to any one of claims 1-6, which is applied to the patient's lungs via a metered dose inhaler . 7. The pharmaceutical composition of any one of claims 1-6, which is applied to the patient's lungs via a dry powder inhaler .

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